2-iminoimidazole derivatives (2)

ABSTRACT

A 2-iminoimidazole derivative represented by the formula: 
                         
{wherein R 1 , R 2  and R 3  represent hydrogen, optionally substituted C 1-6  alkyl, etc.; R 6  represents hydrogen, C 1-6  alkyl, C 1-6  alkyloxycarbonyl, etc.; Y 1  represents a single bond, —CH 2 —, etc.; Y 2  represents a single bond, —CO—, etc.; and Ar represents hydrogen, a group represented by the formula:
 
                         
[wherein R 10 –R 14  represent hydrogen, C 1-6  alkyl, hydroxyl, C 1-6  alkoxy, etc., and R 11  and R 12  or R 12  and R 13  may bond together to form a 5- to 8-membered heterocycle], etc.}or salt thereof.

PRIORITY INFORMATION

The present application claims the benefit under 35 U.S.C. § 371 ofInternational Application No.: PCT/JP02/03950 (published PCT applicationNo. WO 02/088092), filed 19 Apr. 2002, which claims priority to JapanesePatent Application Nos.: 2001-121829, filed 19 Apr. 2001, and2001-269422, filed 5 Sep. 2001, the entire contents of each of theseapplications are hereby incorporated herein by reference.

BACKGROUND OF THE INVENTION

A recent approach for thrombosis has involved inhibiting thrombin enzymeactivity, and compounds used for this purpose have included heparin, lowmolecular weight heparin, hirudin, argatroban, hirulog and the like. Allsuch compounds inhibit the enzyme activity of thrombin, and work byinhibiting fibrin blood clot formation without specifically inhibitingthe effect of thrombin on cells. Bleeding tendency is therefore a commonside effect encountered in the clinic. The role of thrombin inthrombosis is not limited to its blood clotting activity, as it isbelieved to also participate in platelet aggregation at sites ofvascular injury occurring as a result of the activation of plateletthrombin receptor.

Another approach for thrombosis has been the use of intravenousinjection agents such as Abciximab, Eptifibatide and Tirofiban, asGPIIb/IIIa receptor antagonists. These compounds, while exhibitingpowerful anti-thrombotic effects by suppressing platelet aggregationinduced by various stimulation such as thrombin, ADP, collagen, PAF orthe like, also produce a bleeding tendency as a side effect similarly tothrombin enzyme activity inhibitors. For this reason, no such compoundshave yet been marketed, although their development as oral agentscontinues to progress.

Restenosis is a vascular hyperproliferative response to vascular wallinjury induced by invasive treatment such as coronary angioplasty, andthis phenomenon may be provoked by the direct or indirect effect ofthrombin on cells. Platelets adhere to injured blood vessels, leading torelease of growth factors and eliciting proliferation of smooth musclecells. Smooth muscle cells may also be affected indirectly by the actionof thrombin on endothelial cells. Also, platelet adhesion occurs andprocoagulant activity increases at sites of vascular injury. Smoothmuscle cells can undergo further direct stimulation due to the highlocal thrombin concentration which is produced at such sites. Whilerecent studies using the powerful thrombin inhibitor hirudin havesuggested that thrombin induces cell proliferation during the process ofrestenosis, it has not yet been determined whether the thrombin effectis direct or indirect (Sarembock et al., Circulation 1992, 84: 232–243).Despite the implication of the cellular effects of thrombin in a varietyof pathological symptoms, no therapeutically active substance is knownwhich specifically blocks such effects.

The thrombin receptor (PAR1) has recently been cloned (Vu et al., Cell,1991, 64: 1057–1068), opening an important door to development ofsubstances which target cellular thrombin receptors. Detailedexamination of the amino acid sequence of this thrombin receptor hasrevealed a thrombin binding site and hydrolysis site located in the 100residue amino terminal domain of the receptor. Later research by aminoacid mutation in the receptor has established that limited hydrolysis ofthis portion of the thrombin receptor by thrombin is necessary forreceptor activation (Vu et al., Nature, 1991, 353: 674–677). A syntheticpeptide corresponding to the amino acid sequence newly generated byhydrolysis of the thrombin receptor (the synthetic peptide is known as“thrombin receptor activating peptide”, or TRAP) can activate receptorswhich have not been hydrolyzed by thrombin. This suggests that thecleavage of the receptor, the new amino acid sequence generated at theamino terminal (known as the “tethered ligand peptide”) functions as theligand and interacts with the distal binding site. Further studies ofTRAP have confirmed homology of the thrombin receptors present inplatelet, endothelial cell, fibroblast and smooth muscle cell (Hung etal., J. Cell. Biol. 1992, 116: 827–832; and Ngaiza, Jaffe, Biochem.Biophys. Res. Commun. 1991, 179: 1656–1661).

Research on the structure activity relationship of TRAP suggests thatthe pentapeptide Phe-Leu-Leu-Arg-Asn is a weak antagonist for plateletthrombin receptors activated by either thrombin or TRAP (Vassallo. etal., J. Biol. Chem., 1992, 267: 6081–6085 (1992)). Different approachesto receptor antagonism have also been examined by other groups. One ofthese approaches has been an attempt to prepare antibodies for thethrombin binding domain of the thrombin receptor. Such antibodiesspecifically and effectively suppress activation of platelets bythrombin, and act as thrombin receptor antagonists (Hung et al., J.Clin. Invest. 1992, 89: 1350–1353). Another approach has been thedevelopment of peptide derivatives from TRAP (Steven M. S., J. Med.Chem. 1996, 39: 4879–4887; William J. H., Bioorg. Med. Chem. Lett. 1998,8: 1649–1654; and David F. M., Bioorg. Med. Chem. Lett. 1999, 9:255–260). Yet another approach has been the development of low molecularweight compounds discovered by high throughput screening using variousassay systems such as receptor binding (Andrew W. S. et al., Bioorg. MedChem. Lett. 1999, 9: 2073–2078; Scherig Plough WO99/26943; and Halord S.et al., ACS meeting in October 2001).

DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE INVENTION

Compounds having antagonistic action on thrombin receptors are expectedto exhibit excellent effects for therapy or prevention of diseasesassociated with thrombin, and therefore offer promise for effectivetherapy or prevention of, for example, thrombosis, vascular restenosis,deep venous thrombosis, pulmonary embolism, cerebral infarction, heartdiseases, disseminated intravascular coagulation, hypertension,inflammatory diseases, rheumatism, asthma, glomerulonephritis,osteoporosis, neurological diseases, malignant tumors, and the like. Ithas been highly desired to provide thrombin receptor antagonists whichare satisfactory in numerous aspects including pharmacological activity,thrombin receptor specificity, safety, dosage and oral efficacy.

However, the conventional thrombin receptor antagonists have beeninadequate in terms of receptor specificity and oral efficacy.

It is therefore an object of the present invention to search for anddiscover compounds having excellent thrombin receptor inhibitingactivity and being therefore useful as thrombin receptor antagonists.

The inventors have completed thorough research in light of suchcircumstances, leading to the synthesis of novel 2-iminoimidazolederivatives represented by the following general formula (I), theresults of which have unexpectedly revealed that these compounds orsalts thereof have excellent thrombin receptor-inhibiting activity andare useful as thrombin receptor antagonists, which culminated in thepresent invention.

<1> In one aspect, the present invention provides a compound representedby the formula:

{wherein R¹, R² and R³ may be the same or different and eachindependently represents (1) hydrogen, (2) cyano, (3) halogen or (4) agroup selected from Substituent Group A below, and R¹ and R² may bondtogether to form a 5-membered ring; R⁶ represents (1) hydrogen, (2) C₁₋₆alkyl, (3) acyl, (4) carbamoyl, (5) hydroxyl, (6) C₁₋₆ alkoxy, (7) C₁₋₆alkyloxycarbonyloxy, (8) C₃₋₈ cycloalkyl, (9) C₁₋₆ alkyloxycarbonyloptionally substituted with acyloxy or (10) a C₆₋₁₄ aromatic hydrocarbonring group or a 5- to 14-membered aromatic heterocyclic group (each ofthe foregoing members being optionally substituted with at least onegroup selected from Substituent Group E below); Y¹ represents a singlebond, —(CH₂)_(m)—, —CR⁸—, —CR⁸R⁹—, —CH₂CO—, —NR⁸—, —SO—, —SO₂—, —CO—,—CONR⁸— or —SO₂NR⁸— [wherein m represents an integer of 1 to 3, and R⁸and R⁹ are the same or different and each independently representshydrogen, halogen, C₁₋₆ alkyl, carboxyl or C₁₋₆ alkoxycarbonyl]; Y²represents a single bond, O, N, —(CH₂)_(m)—, —CR⁸—, CR⁸R⁹—, —CO—, —SO—,—SO₂— or —C(═N—OR⁸)— [wherein m, R₈ and R⁹ have the same definitionsgiven above]; and Ar represents (1) hydrogen, (2) a group represented bythe formula:

[wherein R¹⁰, R¹¹, R¹², R¹³ and R¹³ are the same or different and eachindependently represents (1) hydrogen, (2) cyano, (3) halogen, (4) nitroor (5) a group selected from Substituent Group B below, and R¹¹ and R¹²or R¹² and R¹³ may bond together to form a 5- to 8-membered heterocycleoptionally having 1 to 4 hetero atoms selected from N, S and O andoptionally substituted with at least one group selected from SubstituentGroup F below] or (3) a 5- to 14-membered aromatic heterocyclic groupoptionally substituted with at least one group selected from SubstituentGroup G below.

<Substituent Group A> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, alkylidene, C₂₋₆ alkenyl, C₂₋₆ alkynyl, acyl,carboxyl, carbamoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,hydroxyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyloxy, amino, C₁₋₆ alkylamino, C₃₋₈cycloalkylamino, acylamino, sulfonylamino, sulfonyl, sulfamoyl, C₃₋₈cycloalkyl, a 5- to 14-membered non-aromatic heterocyclic group, a C₆₋₁₄aromatic hydrocarbon ring group and a 5- to 14-membered aromaticheterocyclic group, each of the foregoing members being optionallysubstituted with at least one group selected from Substituent Group A′below;

<Substituent Group A′> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, cyano, acyl,carboxyl, carbamoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,hydroxyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyloxy, amino, C₁₋₆ alkylamino, C₃₋₈cycloalkylamino, acylamino, ureido, ureylene, sulfonylamino, sulfonyl,sulfamoyl, halogen, C₃₋₈ cycloalkyl, a heterocyclic alkyl group, a 5- to14-membered non-aromatic heterocyclic group, a C₆₋₁₄ aromatichydrocarbon ring group and a 5- to 14-membered aromatic heterocyclicgroup, wherein the C₆₋₁₄ aromatic hydrocarbon ring group and the 5- to14-membered aromatic heterocyclic group may be substituted with at leastone group selected from the group consisting of C₁₋₆ alkyl, cyano, acyl,carboxyl, carbamoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,hydroxyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyloxy, nitro, amino, C₁₋₆alkylamino, C₃₋₈ cycloalkylamino, acylamino, ureido, ureylene,sulfonylamino, sulfonyl, sulfamoyl, halogen and C₃₋₈ cycloalkyl;

<Substituent Group B> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, acyl, carboxyl,carbamoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl, C₁₋₆alkoxy, C₃₋₈ cycloalkyloxy, amino, C₁₋₆ aminoalkyl, C₁₋₆ alkylamino,C₃₋₈ cycloalkylamino, acylamino, ureido, sulfonylamino, sulfonyl,sulfamoyl, C₃₋₈ cycloalkyl, a 5- to 14-membered non-aromaticheterocyclic group, a C₆₋₁₄ aromatic hydrocarbon ring group and a 5- to14-membered aromatic heterocyclic group, each of the foregoing membersbeing optionally substituted with at least one group selected fromSubstituent Group B′ below;

<Substituent Group B′> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, oxo, cyano, C₁₋₆cyanoacyl, C₂₋₇ acyl, C₁₋₆ alkanoyl, benzoyl, aralkanoyl, C₁₋₆alkoxyalkylcarbonyl, C₁₋₆ hydroxyalkylcarbonyl, carboxyl, C₁₋₆carboxyalkyl, C₁₋₆ carboxyalkyloxy, carbamoyl, carbamoylalkyloxy, C₁₋₆alkoxycarbonyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₆ alkyl, C₁₋₁₀alkoxycarbonyl-C₁₋₆ alkyloxy, C₁₋₆ monoalkylaminocarbonyl, C₂₋₆dialkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, C₁₋₁₀ alkoxyalkyl, C₁₋₁₀aralkyloxyalkyl, C₁₋₆ hydroxyalkyl, C₃₋₈ cycloalkyloxy, amino, C₁₋₆alkylamino, C₃₋₈ cycloalkylamino, acylamino, ureido, ureylene, C₁₋₆alkylsulfonylamino, phenylsulfonylamino, C₁₋₆ alkylsulfonyl,phenylsulfonyl, C₁₋₆ monoalkylaminosulfonyl, C₂₋₆ dialkylaminosulfonyl,sulfamoyl, halogeno, C₃₋₈ cycloalkyl, a 5- to 14-membered non-aromaticheterocyclic group, a C₆₋₁₄ aromatic hydrocarbon ring group, a 5-to14-membered aromatic heterocyclic group, a heterocyclic aminocarbonylgroup, a heterocyclic aminosulfonyl group and isoxazolinyl, wherein the5- to 14-membered non-aromatic heterocyclic group, the C₆₋₁₄ aromatichydrocarbon ring group, the 5- to 14-membered aromatic heterocyclicgroup and isoxazolinyl may be independently substituted with at leastone group selected from the group consisting of C₁₋₆ alkyl, oxo, cyano,acyl, carboxyl, carbamoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,hydroxyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyloxy, nitro, amino, C₁₋₆aminoalkyl, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₃₋₈ cycloalkylamino,acylamino, ureido, ureylene, alkylsulfonylamino, alkylsulfonyl,sulfamoyl, halogeno and C₃₋₈ cycloalkyl;

<Substituent Group E> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, cyano, acyl, carboxyl, carbamoyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyloxy, amino, C₁₋₆ alkylamino, C₃₋₈ cycloalkylamino, acylamino,ureido, ureylene, sulfonylamino, sulfonyl, sulfamoyl, halogen and C₃₋₈cycloalkyl;

<Substituent Group F> represents moieties selected from the groupconsisting of (1) hydrogen, (2) cyano, (3) halogen, (4) oxo and (5) C₁₋₆alkyl, alkenyl, alkynyl, acyl, C₁₋₆ alkanoyl, carboxyl, carbamoyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyloxy, amino, imino, C₁₋₆ aminoalkyl, C₁₋₆ alkylamino, C₃₋₈cycloalkylamino, acylamino, ureido, sulfonylamino, sulfonyl, sulfamoyl,C₃₋₈ cycloalkyl, a 5- to 14-membered non-aromatic heterocyclic group, aC₆₋₁₄ aromatic hydrocarbon ring group and a 5- to 14-membered aromaticheterocyclic group (each of the foregoing members being optionallysubstituted with at least one group selected from Substituent Group F′below);

<Substituent Group F′> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, oxo, cyano, acyl, carboxyl, carbamoyl, C₁₋₆alkoxycarbonyl, benzyloxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl,C₁₋₆ alkoxy, C₃₋₈ cycloalkyloxy, amino, C₁₋₆ alkylamino, C₃₋₈cycloalkylamino, acylamino, ureido, ureylene, C₁₋₆ alkylsulfonylamino,C₁₋₆ alkylsulfonyl, sulfamoyl, halogeno, C₃₋₈ cycloalkyl, a 5- to14-membered non-aromatic heterocyclic group, a C₆₋₁₄ aromatichydrocarbon ring group and a 5- to 14-membered aromatic heterocyclicgroup;

<Substituent Group G> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, cyano, acyl, carboxyl, carbamoyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, sulfonyl, sulfamoyl, halogenoand C₃₋₈ cycloalkyl.}or salt thereof.

<2> In certain embodiments, the invention provides a compound accordingto <1> or salt thereof, wherein R¹, R² and R³ may be the same ordifferent and each independently represents C₁₋₆ alkyl, C₂₋₆ alkenyl orC₁₋₆ alkoxy, each of the foregoing members being optionally substitutedwith at least one group selected from Substituent Group A″ below:

<Substituent Group A″> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, acyl, carboxyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, a C₆₋₁₄aromatic hydrocarbon ring group and a 5- to 14-membered aromaticheterocyclic group, wherein the C₆₋₁₄ aromatic hydrocarbon ring groupand the 5- to 14-membered aromatic heterocyclic group may be substitutedwith at least one group selected from the group consisting of C₁₋₆alkyl, carboxyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl,C₁₋₆ alkoxy, nitro, C₁₋₆ alkylamino, acylamino, sulfonylamino andhalogen; R⁶ represents a group selected from the group consisting ofhydrogen, C₁₋₆ alkyl and C₁₋₆ alkyloxycarbonyl optionally substitutedwith acyloxy; Y¹ represents a single bond or —(CH₂)_(m)— [wherein mrepresents an integer of 1 to 3]; Y² represents a single bond or —CO—;and Ar represents hydrogen or a group represented by the formula:

[wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are the same or different and eachindependently represents a group selected from the group consisting ofhydrogen, C₁₋₆ alkyl, hydroxyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₈cycloalkylamino, acylamino, a 5- to 14-membered non-aromaticheterocyclic group and C₁₋₆ alkyloxycarbonyloxy, and R¹¹ and R¹² or R¹²and R¹³ may bond together to form a 5- to 8-membered heterocycle (i)optionally having 1 to 4 hetero atoms selected from N, S and O and (ii)optionally substituted with at least one group selected from the groupconsisting of cyano, oxo, and C₁₋₆ alkyl, acyl, C₁₋₆ alkanoyl, carboxyl,carbamoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl, C₁₋₆alkoxy, C₃₋₈ cycloalkyloxy, amino, C₁₋₆ alkylamino, sulfonyl and a 5- to14-membered non-aromatic heterocyclic group (each of the foregoingmembers being optionally substituted with at least one group selectedfrom Substituent Group F″ below:

<Substituent Group F″> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, oxo, cyano, acyl, carboxyl and C₁₋₆ alkoxy].

<3> In certain other embodiments, the invention provides a compoundaccording to <1> or salt thereof, wherein Y¹ is —CH₂—.

<4> In certain other embodiments, the invention provides a compoundaccording to <1> or salt thereof, wherein Y² is —CO—.

<5> In certain other embodiments, the invention provides a compoundaccording to <1> or salt thereof, wherein Y¹ is —CH₂— and Y² is —CO—.

<6> In certain other embodiments, the invention provides a compoundaccording to <1> or salt thereof, wherein Y¹ is a single bond, Y² is asingle bond and Ar is hydrogen.

<7> In certain other embodiments, the invention provides a compoundaccording to <1> or salt thereof, wherein Ar is a group represented bythe formula:

[wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ have the same definitions givenabove].

<8> In certain other embodiments, the invention provides a compoundaccording to <7> or salt thereof, wherein R¹⁰ and R¹⁴ are hydrogen.

<9> In certain other embodiments, the invention provides a compoundaccording to <1> or salt thereof, wherein Ar is (1) a group representedby the formula:

[wherein R¹, R¹¹, R¹² R¹³ and R¹⁴ have the same definitions given above]or (2) a 5- to 14-membered aromatic heterocyclic group optionallysubstituted with at least one group selected from Substituent Group Gabove.

<10> In certain other embodiments, the invention provides a compoundaccording to <9> or salt thereof, wherein R¹⁰ and R¹⁴ are hydrogen.

<11> In certain other embodiments, the invention provides a compoundaccording to <1> or salt thereof, wherein Ar is a group represented bythe formula:

[wherein R¹¹ and R¹³ have the same definitions given above, and R¹⁵represents (1) hydrogen or (2) a group selected from Substituent Group Hbelow, and R¹¹ and R¹⁵ may bond together to form a 5- to 8-memberedheterocycle optionally substituted with at least one group selected fromSubstituent Group F above and optionally having 1 or 2 hetero atomsselected from N, S and O.

<Substituent Group H> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, acyl, C₁₋₆alkoxycarbonyl, aminocarbonyl, C₁₋₆ alkylaminocarbonyl, C₃₋₈ cycloalkyl,C₁₋₆ aminoalkyl, sulfonyl, C₃₋₈ cycloalkylamino, a 5- to 14-memberednon-aromatic heterocyclic group, a C₆₋₁₄ aromatic hydrocarbon ring groupand a 5- to 14-membered aromatic heterocyclic group, each of theforegoing members being optionally substituted with at least one groupselected from Substituent Group H′ below;

<Substituent Group H′> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, oxo, cyano, C₁₋₆cyanoalkyl, C₂₋₇ acyl, C₁₋₆ alkanoyl, benzoyl, aralkanoyl, C₁₋₆alkoxyalkylcarbonyl, C₁₋₆ hydroxyalkylcarbonyl, carboxyl, C₁₋₆carboxyalkyl, C₁₋₆ carboxyalkyloxy, carbamoyl, carbamoylalkyloxy, C₁₋₆alkoxycarbonyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₆ alkyl, C₁₋₁₀alkoxycarbonyl-C₁₋₆ alkyloxy, C₁₋₆ monoalkylaminocarbonyl, C₂₋₆dialkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, C₁₋₁₀ alkoxyalkyl, C₁₋₁₀aralkyloxyalkyl, C₁₋₆ hydroxyalkyl, C₃₋₈ cycloalkyloxy, amino, C₁₋₆alkylamino, C₃₋₈ cycloalkylamino, acylamino, ureido, ureylene, C₁₋₆alkylsulfonylamino, phenylsulfonylamino, C₁₋₆ alkylsulfonyl,phenylsulfonyl, C₁₋₆ monoalkylaminosulfonyl, C₂₋₆ dialkylaminosulfonyl,sulfamoyl, halogeno, C₃₋₈ cycloalkyl, a 5- to 14-membered non-aromaticheterocyclic group, a C₆₋₁₄ aromatic hydrocarbon ring group, a 5- to14-membered aromatic heterocyclic group, a heterocyclic aminocarbonylgroup, a heterocyclic aminosulfonyl group and isoxazolinyl, wherein the5- to 14-membered non-aromatic heterocyclic group, the C₆₋₁₄ aromatichydrocarbon ring group, the 5- to 14-membered aromatic heterocyclicgroup and isoxazolinyl may be independently substituted with at leastone group selected from the group consisting of C₁₋₆ alkyl, oxo, cyano,acyl, carboxyl, carbamoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,hydroxyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyloxy, nitro, amino, C₁₋₆aminoalkyl, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₃₋₈ cycloalkylamino,acylamino, ureido, ureylene, alkylsulfonylamino, alkylsulfonyl,sulfamoyl, halogeno and C₃₋₈ cycloalkyl].

<12> In certain other embodiments, the invention provides a compoundaccording to <1> or salt thereof, wherein Ar is a group represented bythe formula:

[wherein R¹¹ and R¹⁵ have the same definitions given above, and R¹⁶represents (1) hydrogen or (2) a group selected from Substituent Group Habove, and R¹¹ and R¹⁵ or R¹⁵ and R¹⁶ may bond together to form a 5- to6-membered heterocycle optionally substituted with at least one groupselected from Substituent Group F above and optionally having 1 or 2hetero atoms selected from N, S and O].

<13> In certain other embodiments, the invention provides a compoundaccording to <1> or salt thereof, wherein Ar is a group represented bythe formula:

[wherein R¹¹ and R¹⁵ have the same definitions given above, and R¹⁷ andR¹⁸ are the same or different and each independently represents (1)hydrogen or (2) a group selected from Substituent Group I below, and R¹¹and R¹⁵, R¹⁵ and R¹⁷, R¹⁵and R¹⁷, R¹⁵ and R¹⁸ or R¹⁷ and R¹⁸ may bondtogether to form a 5- to 8-membered heterocycle optionally substitutedwith at least one group selected from Substituent Group F above andoptionally having 1 or 2 hetero atoms selected from N, S and O.

<Substituent Group I> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, acyl, carbamoyl,C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, C₁₋₆ aminoalkyl, sulfonyl,sulfamoyl, C₃₋₈ cycloalkyl, a 5- to 14-membered non-aromaticheterocyclic group, a C₆₋₁₄ aromatic hydrocarbon ring group and a 5- to14-membered aromatic heterocyclic group, each of the foregoing membersbeing optionally substituted with at least one group selected fromSubstituent Group I′ below;

<Substituent Group I′> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, oxo, cyano, C₁₋₆cyanoalkyl, C₂₋₇ acyl, C₁₋₆ alkanoyl, benzoyl, aralkanoyl, C₁₋₆alkoxyalkylcarbonyl, C₁₋₆ hydroxyalkylcarbonyl, carboxyl, C₁₋₆carboxyalkyl, C₁₋₆ carboxyalkyloxy, carbamoyl, carbamoylalkyloxy, C₁₋₆alkoxycarbonyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₆ alkyl, C₁₋₁₀alkoxycarbonyl-C₁₋₆ alkyloxy, C₁₋₆ monoalkylaminocarbonyl, C₂₋₆dialkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, C₁₋₁₀ alkoxyalkyl, C₁₋₁₀aralkyloxyalkyl, C₁₋₆ hydroxyalkyl, C₃₋₈ cycloalkyloxy, amino, C₁₋₆alkylamino, C₃₋₈ cycloalkylamino, acylamino, ureido, ureylene, C₁₋₆alkylsulfonylamino, phenylsulfonylamino, C₁₋₆ alkylsulfonyl,phenylsulfonyl, C₁₋₆ monoalkylaminosulfonyl, C₂₋₆ dialkylaminosulfonyl,sulfamoyl, halogeno, C₃₋₈ cycloalkyl, a 5- to 14-membered non-aromaticheterocyclic group, a C₆₋₁₄ aromatic hydrocarbon ring group, a 5-to14-membered aromatic heterocyclic group, a heterocyclic aminocarbonylgroup, a heterocyclic aminosulfonyl group and isoxazolinyl, wherein the5- to 14-membered non-aromatic heterocyclic group, the C₆₋₁₄ aromatichydrocarbon ring group, the 5- to 14-membered aromatic heterocyclicgroup and isoxazolinyl may be independently substituted with at leastone group selected from the group consisting of C₁₋₆ alkyl, oxo, cyano,acyl, carboxyl, carbamoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,hydroxyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyloxy, nitro, amino, C₁₋₆aminoalkyl, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₃₋₈ cycloalkylamino,acylamino, ureido, ureylene, alkylsulfonylamino, alkylsulfonyl,sulfamoyl, halogeno and C₃₋₈ cycloalkyl].

<14> In another aspect, the invention provides a pharmaceuticalcomposition comprising a compound according to <1> or salt thereof.

<15> In certain embodiments, the invention provides a compositionaccording to <14>, wherein the composition is useful as a thrombinreceptor antagonist.

<16> In certain other embodiments, the invention provides a compositionaccording to <14>, wherein the composition is useful as a thrombinreceptor PAR1 antagonist.

<17> In certain other embodiments, the invention provides a compositionaccording to <14>, wherein the composition is useful as a plateletaggregation inhibitor.

<18> In certain other embodiments, the invention provides a compositionaccording to <14>, wherein the composition is useful as a proliferationinhibitor for smooth muscle cells.

<19> In certain other embodiments, the invention provides a compositionaccording to <14>, wherein the composition is useful as a proliferationinhibitor for endothelial cells, fibroblasts, nephrocytes, osteosarcomacells, muscle cells, cancer cells and/or glia cells.

<20> In certain other embodiments, the invention provides a compositionaccording to <14>, wherein the composition is useful as a therapeutic orprophylactic agent for thrombosis, vascular restenosis, deep venousthrombosis, pulmonary embolism, cerebral infarction, heart disease,disseminated intravascular coagulation, hypertension, inflammatorydisease, rheumatism, asthma, glomerulonephritis, osteoporosis,neurological disease and/or malignant tumor.

<21> In yet another aspect, the invention provides the use of a compoundaccording to <1> or salt thereof for the manufacture of a thrombinreceptor antagonist.

<22> In certain embodiments, the invention provides the use according to<21>, wherein the thrombin receptor antagonist is a PAR1 receptorantagonist.

<23> In certain other embodiments, the invention provides the use of acompound according to <1> or salt thereof for the manufacture of aplatelet aggregation inhibitor.

<24> In a further aspect, the invention provides a therapeutic methodfor treating or preventing a disease associated with thrombin receptors,comprising administering to a patient suffering from the disease, atherapeutically effective dose of a compound according to <1> or saltthereof thereof.

<25> In certain embodiments, the invention provides a therapeutic methodfor treating or preventing a proliferative disease of endothelial cells,fibroblasts, nephrocytes, osteosarcoma cells, muscle cells, cancer cellsand/or glia cells, comprising administering to a patient suffering fromthe disease, a therapeutically effective dose of a compound according to<1> or salt thereof.

The present invention will now be explained in greater detail.

Several of the structural formulas given for the compounds of theinvention throughout the present specification will represent only aspecific isomer for convenience, but the invention is not limited tosuch specific isomers and encompasses all isomers and isomer mixtures,including geometric isomers, asymmetric carbon-derived optical isomers,stereoisomers and tautomers which are implied by the structures of thecompounds, and any isomer or mixture thereof may be used. The compoundsof the invention therefore include those having asymmetric carbons intheir molecules and existing as optically active forms or racemic forms,and all such compounds are encompassed by the invention withoutrestrictions. There are also no restrictions on any crystallinepolymorphism of the compounds, and any crystal forms may be used aloneor in mixtures. The compounds of the invention and their salts may alsobe in the form of anhydrides or solvates such as hydrates, and all suchforms are included within the scope of the claims of the presentspecification. Metabolites of the compounds of the invention produced bydegradation in the body, as well as prodrugs of the compounds of theinvention and their salts, are also encompassed within the scope of theclaims of the present specification.

The symbols and terms used throughout the present specification will nowbe defined, with a more detailed description of the invention.

The term “and/or” as used throughout the present specification carriesthe meaning of both “and” and “or”.

The term “halogen” used throughout the present specification refers toan atom such as fluorine, chlorine, bromine or iodine, and preferablyfluorine, chlorine or bromine.

The term “C₁₋₆ alkyl” used throughout the present specification refersto an alkyl group of 1 to 6 arbons, such as, for example, linear orbranched alkyl groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-ethylpropyl,n-hexyl, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl,1,1,2-trimethylpropyl, 1-propylpropyl, 1-methylbutyl, 2-methylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl and3-methylpentyl, and more preferably methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, tert-butyl and n-pentyl.

The term “C₂₋₆ alkenyl” used throughout the present specification refersto an alkenyl group of 2 to 6 carbons, such as, for example, vinyl,allyl, 1-propenyl, 2-propenyl, isopropenyl, 2-methyl-1-propenyl,3-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-propenyl,1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 1-hexenyl, 1,3-hexanedienyland 1,6-hexanedienyl.

The term “C₂₋₆ alkynyl” used throughout the present specification refersto an alkynyl group of 2 to 6 carbons, such as, for example, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,3-methyl-1-propynyl, 1-ethynyl-2-propynyl, 2-methyl-3-propynyl,1-pentynyl, 1-hexynyl, 1,3-hexanediynyl and 1,6-hexanediynyl.

The term “C₃₋₈ cycloalkyl” used throughout the present specificationrefers to a cycloalkyl group composed of 3 to 8 carbons, and as examplesthere may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

The term “C₃₋₈ cycloalkenyl” used throughout the present specificationrefers to a C₃₋₈ cycloalkenyl group composed of 3 to 8 carbons, such as,for example, cyclopropen-1-yl, cyclopropen-3-yl, cyclobuten-1-yl,cyclobuten-3-yl, 1,3-cyclobutadien-1-yl, cyclopenten-1-yl,cyclopenten-3-yl, cyclopenten-4-yl, 1,3-cyclopentadien-1-yl,1,3-cyclopentadien-2-yl, 1,3-cyclopentadien-5-yl, cyclohexen-1-yl,cyclohexen-3-yl, cyclohexen-4-yl, 1,3-cyclohexadien-1-yl,1,3-cyclohexadien-2-yl, 1,3-cyclohexadien-5-yl, 1,4-cyclohexadien-3-yl,1,4-cyclohexadien-1-yl, cyclohepten-1-yl, cyclohepten-3-yl,cyclohepten-4-yl, cyclohepten-5-yl, 1,3-cyclohepten-2-yl,1,3-cyclohepten-1-yl, 1,3-cycloheptadien-5-yl, 1,3-cycloheptadien-6-yl,1,4-cycloheptadien-3-yl, 1,4-cycloheptadien-2-yl,1,4-cycloheptadien-1-yl, 1,4-cycloheptadien-6-yl,1,3,5-cycloheptatrien-3-yl, 1,3,5-cycloheptatrien-2-yl,1,3,5-cycloheptatrien-1-yl, 1,3,5-cycloheptatrien-7-yl, cycloocten-1-yl,cycloocten-3-yl, cycloocten-4-yl, cycloocten-5-yl,1,3-cyclooctadien-2-yl, 1,3-cyclooctadien-1-yl, 1,3-cyclooctadien-5-yl,1,3-cyclooctadien-6-yl, 1,4-cyclooctadien-3-yl, 1,4-cyclooctadien-2-yl,1,4-cyclooctadien-1-yl, 1,4-cyclooctadien-6-yl, 1,4-cyclooctadien-7-yl,1,5-cyclooctadien-3-yl, 1,5-cyclooctadien-2-yl,1,3,5-cyclooctatrien-3-yl, 1,3,5-cyclooctatrien-2-yl,1,3,5-cyclooctatrien-1-yl, 1,3,5-cyclooctatrien-7-yl,1,3,6-cyclooctatrien-2-yl, 1,3,6-cyclooctatrien-1-yl,1,3,6-cyclooctatrien-5-yl and 1,3,6-cyclooctatrien-6-yl.

The term “C₁₋₆ alkoxy” used throughout the present specification refersto an alkoxy group of 1 to 6 carbons, such as, for example, methoxy,ethoxy, n-propoxy, iso-propoxy, sec-propoxy, n-butoxy, iso-butoxy,sec-butoxy, tert-butoxy, n-pentyloxy, iso-pentyloxy, sec-pentyloxy,n-hexoxy, iso-hexoxy, 1,1-dimethylpropyloxy, 1,2-dimethylpropoxy,2,2-dimethylpropyloxy, 2-ethylpropoxy, 1-methyl-2-ethylpropoxy,1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, 1,1,2-trimethylpropoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 2,2-dimethylbutoxy,2,3-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2-ethylbutoxy,1,3-dimethylbutoxy, 2-methylpentoxy, 3-methylpentoxy and hexyloxy.

The term “C₂₋₆ alkenyloxy” used throughout the present specificationrefers to an alkenyloxy group of 2 to 6 carbons, such as, for example,vinyloxy, allyloxy, 1-propenyloxy, 2-propenyloxy, isopropenyloxy,2-methyl-1-propenyloxy, 3-methyl-1-propenyloxy, 2-methyl-2-propenyloxy,3-methyl-2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-butenyloxy,1-pentenyloxy, 1-hexenyloxy, 1,3-hexanedienyloxy and1,6-hexanedienyloxy.

The term “acyl” used throughout the present specification refers to anatomic group derived by removing the OH group from a carboxyl group of acarboxylic acid, and it is preferably a C₂₋₇ acyl group (an atomic groupderived by removing the OH group from a carboxyl group of a C₂₋₇carboxylic acid (more preferably fatty acid)), of which examples includeacetyl, propionyl, butyroyl and benzoyl.

The term “C₆₋₁₄ aromatic hydrocarbon ring group” used throughout thepresent specification refers to an aromatic hydrocarbon ring groupcomposed of 6 to 14 carbons, and includes monocyclic groups as well asfused rings such as bicyclic and tricyclic groups. Examples includephenyl, indenyl, 1-naphthyl, 2-naphthyl, azulenyl, heptalenyl, biphenyl,indacenyl, acenaphthyl, fluorenyl, phenalenyl, phenanthrenyl,anthracenyl, cyclopentacyclooctenyl and benzocyclooctenyl.

The term “5- to 14-membered aromatic heterocyclic group” used throughoutthe present specification refers to a monocyclic, bicyclic or tricyclic5- to 14-membered aromatic heterocyclic group comprising one or morehetero atoms selected from the group consisting of nitrogen, sulfur andoxygen. Examples include (i) nitrogen-containing aromatic heterocyclicgroups such as pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazolyl, tetrazolyl, benzotriazolyl, pyrazolyl, imidazolyl,benzimidazolyl, indolyl, isoindolyl, indolidinyl, purinyl, indazolyl,quinolyl, isoquinolyl, quinolidyl, phthalazyl, naphthylidinyl,quinoxalyl, quinazolinyl, cinnolinyl, pteridinyl, imidazotriazinyl,pyrazinopyridazinyl, acridinyl, phenanthridinyl, carbazolyl,carbazolinyl, perimidinyl, phenanthrolinyl, phenacenyl,imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl,pyrazolopyridinyl, etc.; (ii) sulfur-containing aromatic heterocyclicgroups such as thienyl, benzothienyl, etc.; (iii) oxygen-containingaromatic heterocyclic groups such as furyl, pyranyl, cyclopentapyranyl,benzofuryl, isobenzofuryl, etc.; and (iv) aromatic heterocyclic groupscontaining 2 or more different hetero atoms, such as thiazolyl,isothiazolyl, benzothiazolyl, benzothiadiazolyl, phenothiazinyl,isoxazolyl, furazanyl, phenoxazinyl, oxazolyl, isoxazoyl, benzoxazolyl,oxadiazolyl, pyrazoloxazolyl, imidazothiazolyl, thienofuranyl,furopyrrolyl, pyridoxazinyl, etc.

The term “5- to 14-membered non-aromatic heterocyclic group” usedthroughout the present specification refers to a monocyclic, bicyclic ortricyclic 5- to 14-membered non-aromatic heterocyclic group comprisingone or more hetero atoms selected from the group consisting of nitrogen,sulfur and oxygen. Examples include pyrrolidyl, pyrrolyl, piperidyl,piperazyl, imidazolyl, pyrazolidyl, imidazolidyl, morpholyl,tetrahydrofuryl, tetrahydropyranyl, aziridinyl, oxiranyl andoxathiolanyl. Non-aromatic heterocyclic groups also include a pyridonering-derived group, and a non-aromatic fused ring (for example, aphthalimide ring-derived group and a succinimide ring-derived group).

The term “5- to 8-membered heterocycle” used throughout the presentspecification refers to a 5- to 8-membered aromatic or non-aromaticheterocycle.

The term “aryl” used throughout the present specification refers to anatomic group remaining after elimination of one hydrogen atom bonded tothe ring of the aromatic hydrocarbon. Examples include phenyl, tolyl,xylyl, biphenyl, naphthyl, anthoryl and phenanthoryl.

The term “alkylidene” used throughout the present specification refersto a divalent group derived by the loss of two hydrogen atoms from thesame carbon of an aliphatic hydrocarbon (preferably a C₁₋₆ alkane).Examples include ethylidene and the like.

The expression “optionally substituted” appearing throughout the presentspecification has the same meaning as “having one or multiplesubstituents in any desired combination at substitutable positions”.

The term “hetero atom” used throughout the present specification refersspecifically to oxygen, sulfur, nitrogen, phosphorus, arsenic, antimony,silicon, germanium, tin, lead, boron, mercury and the like, andpreferably oxygen, sulfur and nitrogen.

Throughout the present specification, the prefix “n-” signifies a normaltype or primary substituent, “sec-” signifies a secondary substituent,“t-” signifies a tertiary substituent and “i-” signifies an iso typesubstituent.

The definitions of ring R¹, R², R³, R⁶, Y¹, Y² and Ar in the compoundsof the invention represented by general formula (I) above are asexplained above. In certain exemplary embodiments, R¹, R² and R³ may bethe same or different and each is (i) C₁₋₆ alkyl, (ii) C₂₋₆ alkenyl or(iii) C₁₋₆ alkoxy, each of the foregoing members being optionallysubstituted with at least one group selected from Substituent Group A″below, with (i) being more preferred:

<Substituent Group A″> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, acyl, carboxyl, C₁₋₆ alkoxycarbonyl, C₁₋₆alkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, a C₆₋₁₄aromatic hydrocarbon ring group and a 5- to 14-membered aromaticheterocyclic group, wherein the C₆₋₁₄ aromatic hydrocarbon ring groupand the 5- to 14-membered aromatic heterocyclic group may be substitutedwith at least one group selected from the group consisting of C₁₋₆alkyl, carboxyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl,C₁₋₆ alkoxy, nitro, C₁₋₆ alkylamino, acylamino, sulfonylamino andhalogen.

In certain embodiments, R⁶ is a group selected from the group consistingof hydrogen, C₁₋₆ alkyl and C₁₋₆ alkyloxycarbonyl optionally substitutedwith acyloxy.

In certain other embodiments, Y¹ is a single bond or —(CH₂)_(m)—[wherein m represents an integer of 1 to 3] and Y² is a single bond or—CO—, there being more preferred (i) the combination that Y¹ is —CH₂—and Y² is —CO—, and (ii) the combination that Y¹ and Y² are each asingle bond.

In certain other embodiments, Ar is hydrogen or a group represented bythe formula:

[wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ have the same definitions givenabove].

(i) When Y¹ is —CH₂— and Y² is —CO—, Ar is preferably a grouprepresented by general formula (II) above, and (ii) when Y¹ and Y² areeach a single bond, Ar is preferably hydrogen.

In certain embodiments, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are the same ordifferent and are each a group selected from the group consisting ofhydrogen, C₁₋₆ alkyl, hydroxyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₈cycloalkylamino, acylamino, a 5- to 14-membered non-aromaticheterocyclic group and C₁₋₆ alkyloxycarbonyloxy, and more preferably R¹⁰and R¹⁴ are each hydrogen. In certain other embodiments, R¹¹ and R¹² orR¹² and R¹³ may bond together to form a 5- to 8-membered heterocycle (i)optionally having 1 to 4 hetero atoms selected from N, S and O and (ii)optionally substituted with at least one group selected from the groupconsisting of cyano, oxo, and C₁₋₆ alkyl, acyl, C₁₋₆ alkanoyl, carboxyl,carbamoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl, C₁₋₆alkoxy, C₃₋₈ cycloalkyloxy, amino, C₁₋₆ alkylamino, sulfonyl and a 5- to14-membered non-aromatic heterocyclic group (each of the foregoingmembers being optionally substituted with at least one group selectedfrom Substituent Group F″ below:

<Substituent Group F″> represents moieties selected from the groupconsisting of C₁₋₆ alkyl, oxo, cyano, acyl, carboxyl and C₁₋₆ alkoxy).

In certain embodiments, an exemplary group for (ii) above is the groupconsisting of cyano, oxo, C₁₋₆ alkyl, cyano-C₁₋₆ alkyl, C₁₋₆ acyl,carboxyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl andC₁₋₆ alkoxy.

In certain other embodiments, R¹⁰ and R¹⁴ are each hydrogen, and Ar is agroup represented by the formula:

[wherein R¹¹ and R¹³ have the same definitions given above, R¹⁵represents (1) hydrogen or (2) a group selected from Substituent Group Habove, and R¹¹ and R¹⁵ may bond together to form a 5- to 8-memberedheterocycle optionally substituted with at least 1 group selected fromSubstituent Group F above and optionally having 1 or 2 hetero atomsselected from N, S and O];

a group represented by the formula:

[wherein R¹¹ and R¹⁵ have the same definitions given above, R¹⁶represents (1) hydrogen or (2) a group selected from Substituent Group Habove, and R¹¹ and R¹⁵ or R¹⁵ and R¹⁶ may bond together to form a 5- to6-membered heterocycle optionally substituted with at least one groupselected from Substituent Group F above and optionally having 1 or 2hetero atoms selected from N, S and O];

and a group represented by the formula:

[wherein R¹¹ and R¹⁵ have the same definitions given above, R¹⁷ and R¹⁸are the same or different and each independently represents (1) hydrogenor (2) a group selected from Substituent Group I, and R¹¹ and R¹⁵, R¹⁵and R¹⁷, R¹⁵ and R¹⁸ or R¹⁷ and R¹⁸ may bond together to form a 5- to8-membered heterocycle optionally substituted with at least one groupselected from Substituent Group F above and optionally having 1 or 2hetero atoms selected from N, S and O].

The term “salt” used throughout the present specification is notparticularly restrictive so long as the salt is formed with a compoundof the invention and is pharmacologically acceptable. Examples includehydrogen halide acid salts (for example, hydrofluoride, hydrochloride,hydrobromide and hydroiodide), inorganic acid salts (for example,sulfate, nitrate, perchlorate, phosphate, carbonate and bicarbonate),organic carboxylate (for example, acetate, trifluoroacetate, oxalate,maleate, tartarate, fumarate and citrate), organosulfonate (for example,methanesulfonate, trifluoromethanesulfonate, ethanesulfonate,benzenesulfonate, toluenesulfonate and camphorsulfonate), amino acidsalts (for example, aspartate and glutamate), quaternary amine salts,alkali metal salts (for example, sodium salts and potassium salts) oralkaline earth metal salts (for example, magnesium salts and calciumsalts). In certain embodiments, salts of the invention are“pharmacologically acceptable salts” such as hydrochloride, oxalate,trifluoroacetate and the like.

Production processes for compounds of the invention and salts thereofwill now be described. Various processes are possible for production ofthe compounds of the invention represented by the general formula (I)above and their salts, and the synthesis may be carried out by ordinaryorganic synthesis methods. The following representative productionprocesses will now be presented.

[Representative Production Processes]

An exemplary synthetic method for the preparation of2-iminobenzimidazole derivatives is shown in Production Process L below.

<Production Process L>

Production Process L is an exemplary synthetic method for imidazolederivatives.

This scheme is an exemplary synthetic method for an imidazolederivative. In the formulas, Ar has the same definition as for thecompounds represented by formula (I) in claim 1. R1 represents hydrogen,halogeno, cyano, trifluoromethyl, carboxyl, alkoxycarbonyl, optionallysubstituted alkyl, optionally substituted alkoxy, optionally substitutedamino, optionally substituted aminocarbonyl, optionally substitutedphenyl or an aromatic heterocyclic group. R2 has the same definition asR1 in the compounds represented by formula (I) in claim 1.

Step 1 represents a step of alkylation. Compound (L1-b) is obtained byreaction with a halide, mesylate or tosylate according to the methoddescribed in Anthony Long et al., Synthesis, 709 (1991), J. Med. Chem.,34, 1400 (1991) or Yasuo Kikugawa, Synthesis, 124 (1981).

Step 2 represents a step of reduction of the nitro group. Compound(L1-c) is obtained by a method of reaction in tetrahydrofuran, ethylacetate, methanol or ethanol in the presence of palladium-carbon under ahydrogen atmosphere, or by a method of reaction with iron in analcohol-water solvent in the presence of ammonium chloride, at thereflux temperature of the solvent.

Step 3 represents a step of alkylation, wherein compound (L1-d) may beobtained as a hydrobromide salt by dissolving compound (L1-c) and a2-haloethanone derivative in dimethylformamide, acetonitrile, alcohol orthe like and selecting the conditions from room temperature to refluxtemperature, depending on the compound. As an alternative method,compound (L1-c) may be reacted with sodium hydride in tetrahydrofuran ordimethylformamide and then reacted with a 2-haloethanone derivative atroom temperature or while cooling on ice to yield a salt-free form ofcompound (L1-d), prior to treatment with an acid. Preferably, anammonium salt may be obtained by reaction with a 5 N hydrochloric acidin an organic solvent or with 5 N hydrobromic acid in acetic acid.

This scheme is an exemplary synthetic method for an imidazole derivativeincluding a reaction for formation of the imidazole ring. In theformulas, Ar has the same definition as for the compounds represented byformula (I) in claim 1. R1 has the same definition as R1 in Scheme L-1.R3 has the same definition as R¹ of the compounds represented by formula(I) in claim 1.

Step 1 represents a step of reductive amination, wherein reaction withan amine is conducted in tetrahydrofuran or alcohol-acetic acid underdehydrating conditions. The obtained imine derivative is reacted withsodium borohydride, sodium cyanoborohydride or sodiumtriacetoxyborohydride in the aforementioned solvent to yield compound(L2-b).

Step 2 represents a step of forming an imidazole ring, wherein compound(L2-c) is obtained by the method described in F. Compernolle et al., J,Heterocycl. Chem., 19, 1403, 1982 or Lipinski C. A. et al., J. Med.Chem. 29, 2154, (1986), or by deacetalation under acidic conditions inethanol, methanol or acetone, followed by reaction with a cyanamideafter rendering the reaction mixture basic.

Step 3 represents a step of alkylation, wherein compound (L2-d) may beobtained as a hydrobromide salt by dissolving compound (L2-c) and a2-haloethanone derivative in dimethylformamide, acetonitrile, alcohol orthe like and selecting the conditions from room temperature to refluxtemperature, depending on the compound. As an alternative method,compound (L2-d) may be reacted with sodium hydride in tetrahydrofuran ordimethylformamide and then reacted with a 2-haloethanone derivative atroom temperature or while cooling on ice to yield a salt-free form ofcompound (L2-d), prior to treatment with an acid. Preferably, anammonium salt may be obtained by reaction with a 5 N hydrochloric acidin an organic solvent or with 5 N hydrobromic acid in acetic acid.

This scheme is an exemplary synthetic method for an imidazole derivativeincluding a reaction for formation of the imidazole ring. In theformulas, Ar has the same definition as for the compounds represented byformula (I) in claim 1. R1 has the same definition as R1 in Scheme L-1.R2 has the same definition as R¹ of the compounds represented by formula(I) in claim 1.

Step 1 represents a step of amination of an epoxy derivative. Compound(L3-b) is obtained by reaction with an amine in a solvent such asacetonitrile, ethanol, methanol, tetrahydrofuran or the like, at roomtemperature or reflux temperature.

Step 2 represents a step of protecting the amino group with a carbamate.Compound (L3-c) is obtained by reaction with di-tert-butyl dicarbonatein a solvent such as acetonitrile or tetrahydrofuran in the presence oftriethylamine.

Step 3 represents a step of oxidizing the hydroxyl group, whereincompound (L3-d) is obtained according to the method described in N.Cohen et al., J. Am. Chem. Soc., 105, 3661 (1983), or D. Swern et al,Synthesis 165, (1981).

Step 4 represents a step of forming an imidazole ring, wherein compound(L3-e) is obtained by the method described in F. Compernolle et al., J.Heterocycl. Chem., 19, 1403, 1982 or Lipinski C. A. et al., J. Med.Chem. 29, 2154, (1986), or by deprotection under acidic conditions inethanol, methanol or acetone, followed by reaction with a cyanamideafter rendering the reaction mixture basic.

Step 5 represents a step of alkylation, wherein compound (L3-f) may beobtained as a hydrobromide salt by dissolving compound (L3-e) and a2-haloethanone derivative in dimethylformamide, acetonitrile, alcohol orthe like and selecting the conditions from room temperature to refluxtemperature, depending on the compound. As an alternative method,compound (L3-e) may be reacted with sodium hydride in tetrahydrofuran ordimethylformamide and then reacted with a 2-haloethanone derivative atroom temperature or while cooling on ice to yield a salt-free form ofcompound (L3-f), prior to treatment with an acid. Preferably, anammonium salt may be obtained by reaction with a 5 N hydrochloric acidin an organic solvent or with 5 N hydrobromic acid in acetic acid.

This scheme is an exemplary synthetic method for an imidazole derivativeincluding a reaction for formation of the imidazole ring. In theformulas, Ar has the same definition as for the compounds represented byformula (I) in claim 1. R1 represents optionally substituted alkyl,optionally substituted alkoxy or optionally substituted amino.

Step 1 represents a step of protecting the amino group with a carbamate.Compound (L4-b) is obtained by reaction with di-tert-butyl dicarbonatein a solvent such as acetonitrile or tetrahydrofuran in the presence oftriethylamine.

Step 2 represents a step of oxidizing the hydroxyl group, whereincompound (L4-c) is obtained according to the method described in N.Cohen et al., J. Am. Chem. Soc., 105, 3661 (1983), or D. Swern et al,Synthesis 165, (1981).

Step 3 represents a step of forming an imidazole ring, wherein compound(L4-d) is obtained by the method described in F. Compernolle et al., J.Heterocycl. Chem., 19, 1403, 1982 or Lipinski C. A. et al., J. Med.Chem. 29, 2154, (1986), or by deprotection under acidic conditions inethanol, methanol or acetone, followed by reaction with a cyanamideafter rendering the reaction mixture basic.

Step 4 represents a step of alkylation, wherein compound (L4-e) may beobtained as a hydrobromide salt by dissolving compound (L4-d) and a2-haloethanone derivative in dimethylformamide, acetonitrile, alcohol orthe like and selecting the conditions from room temperature to refluxtemperature, depending on the compound. As an alternative method,compound (L4-d) may be reacted with sodium hydride in tetrahydrofuran ordimethylformamide and then reacted with a 2-haloethanone derivative atroom temperature or while cooling on ice to yield a salt-free form ofcompound (L4-e), prior to treatment with an acid. Preferably, anammonium salt may be obtained by reaction in a 5 N hydrochloric acid inan organic solvent or with 5 N hydrobromic acid in acetic acid.

The following are general synthesis methods for the starting materialsused in the production processes described above.

<Production Process AP>

This is a process for synthesis of intermediates (AP1-c), (AP1-d),(AP1-e), (AP2-b), (AP2-c) and (AP2-d) as common starting materials forsynthesis of aminophenol derivatives.

This scheme is an exemplary method for synthesis of compound (AP1-e)from compound (AP1-a). In the formulas, R1 represents hydrogen,optionally substituted alkyl, optionally substituted cycloalkyl oroptionally substituted alkoxy. R2 has the same definition as R6 and R7in Production Process MO.

Step 1 represents a step of Friedel-Crafts acylation. Compound (AP1-b)may be obtained by reacting compound (AP1-a) with acetyl chloride in asolvent such as dichloromethane or toluene, in the presence of a Lewisacid such as aluminum chloride, zinc chloride or tin (II) chloride, at−70° C. to room temperature.

Step 2 represents a step of nitration. Compound (AP1-c) may be obtainedby reaction with fuming nitric acid or concentrated nitric acid in asolvent such as toluene, hexane, ether or acetic anhydride.Alternatively, the reaction may be conducted by generating nitric acidfrom sodium nitrate and hydrochloric acid.

Step 3 represents a step of introducing a substituent R2 having any ofvarious structures at the hydroxyl group of compound (AP1-c). Compound(AP1-d) may be obtained by reaction with a halide, mesylate or tosylatein a solvent such as dimethylformamide, acetonitrile, tetrahydrofuran,dichloromethane or acetone, in the presence of a base such as potassiumcarbonate, cesium carbonate, sodium hydrogencarbonate, trialkylamine, apyridine derivative or sodium hydride. In the formulas, R2 has the samedefinition as R6 in Step 1 of Production Process MO.

Step 4 represents a step of reduction of the nitro group. Compound(AP1-e) may be obtained by reaction in a solvent such astetrahydrofuran, ethyl acetate, methanol or ethanol under a hydrogenatmosphere, in the presence of a catalyst such as palladium-carbon.Alternatively, compound (AP1-e) may be obtained by conducting thereaction in a solvent such as hydrated methanol or hydrated ethanol inthe presence of ammonium chloride, with addition of iron at the refluxtemperature of the solvent.

This scheme is an exemplary method for synthesis of (AP2-d) from(AP1-a). In the formulas, R1 represents hydrogen, optionally substitutedalkyl, optionally substituted cycloalkyl or optionally substitutedalkoxy.

Step 1 represents a step of bromination of the para-position relative tothe phenolic hydroxyl group. Reaction with bromine is conducted in asolvent such as methanol, ethanol or chloroform. Alternatively, compound(AP2-a) may be obtained by reaction with N-bromosuccinimide in a solventsuch as acetonitrile or dimethylformamide.

Step 2 represents a step of nitration. Compound (AP2-b) may be obtainedby reaction with fuming nitric acid or concentrated nitric acid in asolvent such as toluene, hexane, ether or acetic anhydride.Alternatively, the reaction may be conducted by generating nitric acidfrom sodium nitrate and hydrochloric acid.

Step 3 represents a step of introducing a substituent R2 with any ofvarious structures at the hydroxyl group of compound (AP2-b). Compound(AP2-c) may be obtained by reaction with a halide, mesylate or tosylatein a solvent such as dimethylformamide, acetonitrile, tetrahydrofuran,dichloromethane or acetone, in the presence of a base such as potassiumcarbonate, cesium carbonate, sodium hydrogencarbonate, trialkylamine, apyridine derivative or sodium hydride. In the formulas, R2 has the samedefinition as R6 in Step 1 of Production Process MO.

Step 4 represents a step of reduction of the nitro group. Compound(AP2-d) may also be obtained by conducting the reaction in a solventsuch as hydrated methanol or hydrated ethanol in the presence ofammonium chloride, with addition of iron at the reflux temperature ofthe solvent.

The following Production Processes PP to BOL are general productionprocesses for aminophenol derivatives using compounds synthesized byProduction Process AP as the starting materials.

Production Process PP is an exemplary synthetic method for a piperazinederivative.

Step 1 represents a step of treating the amino group of compound (PP-a)with bis(chloroethyl)amine hydrochloride to form a piperazine ring.Preferably, compound (PP-a) is reacted with bis(chloroethyl)aminehydrochloride in 1,2-dichlorobenzene while heating to reflux, and thereaction is conducted while removing the generated hydrogen chloride gasto yield compound (PP-b).

In the formulas, R1 represents hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted alkoxy,optionally substituted alkylamino, etc. R2 represents hydrogen,optionally substituted alkyl, etc.

The formulas in Production Process PP show only a piperazine group, butany 5- to 8-membered ring containing plural nitrogen atoms may beformed, without any restriction to piperazine.

Step 2 represents a step of introducing substituent R3 at the secondaryamine position of the piperazine of compound (PP-b). Compound (PP-b) maybe reacted with reagent R3-X1 (X1=halogen) in an appropriate solventsuch as dichloromethane or tetrahydrofuran, in the presence of aninorganic base such as potassium carbonate or sodium hydrogencarbonateor in the presence of an organic base such as trialkylamine or apyridine derivative to yield R3 introduced compound (PP-c). R3 ofreagent R3-X1 represents optionally substituted alkyl, optionallysubstituted alkyl having cyano on the end or a branch, alkyl havingprotected or substituted carboxylic acid on the end or a branch, alkylhaving protected or substituted hydroxyl on the end or a branch, alkylhaving protected or substituted amino on the end or a branch, optionallysubstituted sulfonyl, optionally substituted acyl, or optionallysubstituted carbamoyl. The reagent used to introduce substituent R3 intocompound (PP-b) may be, instead of R3-X1 mentioned above, di-t-butyldicarbonate or optionally substituted isocyanate. Compound (PP-b) may besubjected to reductive amination using an optionally substitutedaldehyde or ketone and sodium triacetoxyborohydride or sodiumcyanoborohydride for introduction of substituent R3.

Compound (PP-c) obtained by this Production Process may be converted tothe final target compound by Production Process A.

Production Process MO is an exemplary production process for aheterocyclic amino derivative.

Step 1 represents a step of treating the amino group of compound (MO-a)with a reagent represented by Z1-Y1-Y2-Y3-Z2 to form anitrogen-containing ring.

Compound (MO-b) may be obtained by reacting compound (MO-a) with reagentZ1-Y1-Y2-Y3-Z2 in an appropriate solvent such as dimethylformamide,tetrahydrofuran or dichloromethane, in the presence of an inorganic basesuch as potassium carbonate, sodium hydrogencarbonate or cesiumcarbonate or in the presence of an organic base such as trialkylamine ora pyridine derivative.

Z1 and Z2 in the reagent Z1-Y1-Y2-Y3-Z2 represent leaving groups such ashalogen or sulfonate. Y1 and Y3 represent methylene optionallysubstituted with alkyl, alkoxy or the like, carbonyl, carboxyl, sulfonylor amide. Elements to form the main chain at the portion represented by—Y2- include carbon, oxygen, nitrogen and sulfur, and there are noparticular restrictions on the length of the chain. Where possible, theelement forming the —Y2- main chain may also have as a substituentoptionally substituted alkyl, optionally substituted alkoxy, optionallysubstituted alkoxyalkyl, optionally substituted hydroxyalkyl, hydroxy,carbonyl, optionally protected or substituted carboxyl, optionallyprotected or substituted carboxyalkyl, optionally protected orsubstituted amine, optionally protected or substituted aminoalkyl, etc.An oxo group may also be present on the —Y2- main chain to formcarbonyl, sulfonyl or sulfinyl together with carbon or sulfur on themain chain.

In the formulas, R1 has the same definition as R1 in Step 1 ofProduction Process PP. R6 represents optionally substituted alkyl, aprotecting group for hydroxyl, such as methoxymethyl, tetrahydropyranylor trialkylsilyl, or alternatively alkyl having cyano at the end or abranch, alkyl having protected or substituted carboxylic acid on the endor a branch, arylalkyl having protected or substituted carboxylic acidon the end or a branch, alkyl having protected or substituted hydroxylon the end or a branch, arylalkyl having protected or substitutedhydroxyl on the end or a branch, alkyl having protected or substitutedamino on the end or a branch, arylalkyl having protected or substitutedamino on the end or a branch, optionally substituted sulfonyl,optionally substituted acyl, optionally substituted carbamoyl, etc.

Step 2 represents a step of deprotection when R6of compound (MO-b) is aprotecting group for the phenolic hydroxyl group. For example, compound(MO-c) wherein R6 is methoxymethyl may be obtained by treating compound(MO-b) with an acidic mixed solvent such as 5 N hydrochloricacid/acetone or 10% aqueous perchloric acid/tetrahydrofuran.

Step 3 represents a step of introducing a new substituent R7 at thephenolic hydroxyl group of compound (MO-c).

R7 has the same definition as R6 in Step 1 of Production Process MO.

Compound (MO-d) wherein X2 of reagent R7-X2 described below is a leavinggroup such as halogen or sulfonate may be synthesized in the followingmanner. Compound (MO-d) may be obtained by reacting compound (MO-c) withreagent R7-X2 in an appropriate solvent such as dimethylformamide,acetonitrile, diethyl ether, tetrahydrofuran or dichloromethane, in thepresence of an inorganic base such as potassium carbonate, sodiumhydrogencarbonate or cesium carbonate or in the presence of an organicbase such as trialkylamine or a pyridine derivative, or in the presenceof sodium hydride.

Compound (MO-d) wherein R7 is methyl may be obtained at a high yield byreacting compound (MO-c) with diazomethane in diethyl ether or withtrimethylsilyldiazomethane inacetonitrile-diisopropylethylamine-methanol.

Compound (MO-d) wherein X2 in reagent R7-X2 is hydroxyl may be obtainedby reacting compound (MO-c) with reagent R7-X2 by the publicly knownMitsunobu reaction in an appropriate solvent such as tetrahydrofuran ortoluene.

In Production Process MO, R6 and R7 may sometimes undergo conversion toa structure which is not defined herein by a method easily predictableby a person skilled in the art at an appropriate stage afterintroduction. Likewise, the —N—Y1-Y2-Y3 (—N) portion obtained bycyclization in Step 1 may sometimes also undergo conversion to astructure which is not defined herein. (Conversion of the —N—Y1-Y2-Y3(—N) portion is described in some of the following Production Processexamples).

Compounds (MO-b), (MO-c) and (MO-d) obtained in this Production Processmay be converted to the final target compounds by Production Process A.

<Production Process PR>

Production Process PR is an exemplary synthetic method for pyrrolidinederivatives.

Scheme PR-1 is an exemplary production scheme whereby the —N—Y1-Y2-Y3(—N) portion obtained by cyclization in Step 1 of Production Process MOmay undergo additional structural conversion. In the formulas, R1 hasthe same definition as R1 in Step 1 of Production Process PP. R10 andR11 have the same definitions as R6 and R7 in Production Process MO.Although only methoxymethyl is mentioned as a protecting group for thephenolic hydroxyl group of compounds (PR1-a) and (PR1-b), there is nolimitation to methoxymethyl.

Step 1 represents a step of introducing a substituent R10 at thehydroxyl group of compound (PR1-a). The reaction is conducted usingreagent R10-X3 in an appropriate alkaline hydrated organic solvent, inthe presence of a phase transfer catalyst. Preferably, compound (PR1-b)is obtained by reaction of reagent R10-X3 with compound (PR1-a) in amixture of 50% aqueous sodium hydroxide and toluene in the presence oftetrabutylammonium bromide. Here, X3 is a leaving group such as halogenor sulfonate.

Step 2 represents a step of treating compound (PR1-b) in the same manneras Step 2 of Production Process MO to yield compound (PR1-c).

Step 3 represents a step of introducing a new substituent R11 at thephenolic hydroxyl group of compound (PR1-c). Compound (PR1-c) may betreated in the same manner as for introduction of R7 in Step 3 ofProduction Process MO to yield R11 introduced compound (PR1-d).

Step 4 represents a step of treating compound (PR1-a) in the same manneras Step 2 of Production Process MO to yield compound (PR1-e).

Step 5 represents a step of selectively introducing substituent R11 onlyat the phenolic hydroxyl group of compound (PR1-e). Utilizing thedifference in reactivity between the two hydroxyl groups of compound(PR1-e), treatment may be carried out in the same manner as forintroduction of R7 in Step 3 of Production Process MO to yield R11introduced compound (PR1-f).

Step 6 represents a step of treating compound (PR1-f) in the same manneras Step 1 of this Scheme PR-1 to yield compound (PR1-d).

Compounds (PR1-b) and (PR1-d) obtained in this Scheme PR-1 may beconverted to the final target compounds by Production Process A.

Scheme PR-2 is another exemplary production scheme whereby the—N—Y1-Y2-Y3 (—N) portion obtained by cyclization in Step 1 of ProductionProcess MO may undergo additional structural conversion. In theformulas, R1 has the same definition as R1 in Step 1 of ProductionProcess PP. R15 and R20 have the same definitions as R6 and R7 inProduction Process MO.

Step 1 represents a step of replacing the hydroxyl group of compound(PR1-a) with a substituent R14 (F or CN). When R14 is fluoro, compound(PR1-a) may be treated with diethylaminosulfur trifluoride (DAST) indichloromethane to yield compound (PR2-a: R14=F). When R14 is cyano, thehydroxyl group of compound (PR1-a) may first be converted to a leavinggroup with an acyl chloride reagent such as methanesulfonyl chloride inan appropriate solvent such as dichloromethane, in the presence of abase such as triethylamine. A hydrogen cyanide salt may then be reactedwith this intermediate to introduce a cyano group. Preferably, theintermediate is added to dimethylformamide and reacted with sodiumcyanide in the presence of tetrabutylammonium iodide to yield compound(PR2-a: R14=CN).

Step 2 represents a step of treating compound (PR2-a)(R14=F or CN) inthe same manner as Step 2 of Production Process MO to yield compound(PR2-b)(R14=F or CN).

Step 3 represents a step of introducing substituent R15 at the phenolichydroxyl group of compound (PR2-b)(R14=F or CN). Compound (PR2-b) may betreated in the same manner as for introduction of R7 in Step 3 ofProduction Process MO to yield R15 introduced compound (PR2-c)(R14=F orCN).

Step 4 represents a step of converting compound (PR2-c) wherein R14=CNto compound (PR2-d) wherein cyano may be converted to carboxyl by alkalihydrolysis. Preferably, compound (PR2-c) wherein R14=CN may be reactedby heating to reflux in a mixed solvent of aqueous sodium hydroxide andethanol to yield compound (PR2-d).

Step 5 represents a step of esterifying or amidating the carboxylic acidgroup of compound (PR2-d) for introduction of a substituent R18 bycommon methods. The carboxylic acid group of compound (PR2-d) may beconverted to an active species by a common method such as an acid mixingmethod using a chloroformic acid ester or an acid chloride method usingoxalyl chloride, and then reacted with an alcohol or amine forconversion to (PR2-e). Alternatively, (PR2-d) may be esterified byreaction with the corresponding alkyl halide reagent in the presence ofan appropriate base or by reaction with di-tert-butyl dicarbonate intert-butyl alcohol in the presence of dimethylaminopyridine. Compound(PR2-d) may also be subjected to dehydration reaction using an alcoholor amine and a peptide-forming condensing agent, for conversion tocompound (PR2-e). The synthesis may also be carried out by othersuitable known reactions. R18 represents amino or alkoxy.

Step 6 represents a step of subjecting compound (PR2-a: R14=CN) toalkali hydrolysis in the same manner as Step 4 followed by treatment inthe same manner as the esterification in Step 5, and then ketalprotection of the carbonyl group of the acetophenone. After convertingcompound (PR2-a: R14=CN) to a carboxylic acid ester, it may be reactedwith a ketalizing reagent such as methyl orthoformate under acidicconditions to yield compound (PR2-f). Preferably, the methylorthoformate is reacted with the carbonyl group in methanol in thepresence of an acid catalyst such as camphorsulfonic acid orp-toluenesulfonic acid and Molecular Sieve 3A, to yield compound(PR2-f).

Step 7 represents a step of reducing the ester group of compound (PR2-f)for conversion to a hydroxymethyl group, and then selectivelydeprotecting only the ketal protection of the carbonyl group of theacetophenone. First, compound (PR2-f) is reacted with an ester-reducingreagent such as lithium aluminum hydride in an appropriate solvent suchas tetrahydrofuran or diethyl ether, for conversion to a hydroxymethylgroup. Next, under mildly acidic conditions, and preferably underconditions with an acetic acid-tetrahydrofuran-water (4:1:1) mixed acidsolvent, the ketal protecting group for the carbonyl group isselectively deprotected while leaving the methoxymethyl group for thephenolic hydroxyl, to yield compound (PR2-g).

Step 8 represents a step of converting the hydroxyl group of compound(PR2-g) to substituent R19 (cyano or various alkoxy).

When R19 is cyano, treatment is carried out in the same manner as forconversion in Step 1 when R14 is cyano, to yield compound (PR2-h)wherein hydroxymethyl of compound (PR2-g) may be converted tocyanomethyl, in which case R19 represents cyano. When R19 is alkoxy,compound (PR2-g) is treated in the same manner as Step 1 of Scheme PR-1to yield compound (PR2-h) for conversion to alkoxy, in which case R19has the same definition as OR10 in Scheme PR-1.

Step 9 represents a step of deprotecting the methoxymethyl group servingas the protecting group for the phenolic hydroxyl group of compound(PR2-h), and then introducing a substituent R20. First, compound (PR2-h)is treated in the same manner as Step 2 of Production Process MO toremove the methoxymethyl group. It is then treated in the same manner asfor introduction of R7 in Step 3 of Production Process MO to yieldcompound R20 introduced (PR2-i).

Compounds (PR2-c), (PR2-e) and (PR2-i) obtained in this Scheme PR-2 maybe converted to the final target compounds by Production Process A.

Scheme PR-3 is an exemplary production scheme whereby the —N—Y1-Y2-Y3(—N) portion obtained by cyclization in Step 1 of Production Process MOmay undergo additional structural conversion. In the formulas, R1 hasthe same definition as R1 in Step 1 of Production Process PP. R23, R24and R25 have the same definitions as R6 and R7 in Production Process MO.

Step 1 represents a step of treating compound (PR3-a) in the same manneras Step 1 of Scheme PR-1 to yield compound (PR3-b) having onesubstituent R24 introduced therein and compound (PR3-c) having twosubstituents R24 introduced therein. Alternatively, when R24 ismethoxymethyl or the like, an excess of methoxymethyl chloride may bereacted with compound (PR3-a) in the presence of diisopropylethylamineto yield compounds (PR3-b) and (PR3-c). Compounds (PR3-b) and (PR3-c)may be separated by silica gel column chromatography.

Step 2 represents a step of treating compound (PR3-b) in the same manneras Step 1 to yield compound (PR3-d) having a newly introducedsubstituent R25.

Step 3 represents a step of stereoinversion of the hydroxyl group ofcompound (PR3-b) to yield compound (PR3-e). Compound (PR3-b) is reactedwith m-nitrobenzenesulfonyl chloride in dichloromethane in the presenceof triethylamine and dimethylaminopyridine. It is then treated withcesium acetate while heating in dimethylsulfoxide to yield ahydroxyl-inverted acetate. This is treated with potassium carbonate inmethanol to yield hydroxyl-inverted compound (PR3-e).

Compounds (PR3-b), (PR3-c) and (PR3-d) obtained in Scheme PR-3 may beconverted to the final target compounds by Production Process A.Compound (PR3-e) may also be treated in the same manner as Step 2 ofthis scheme and then converted to the final target compound byProduction Process A.

Scheme PR-4 is an exemplary production scheme whereby the —N—Y1-Y2-Y3(—N) portion obtained by cyclization in Step 1 of Production Process MOmay undergo additional structural conversion. In the formulas, R1 hasthe same definition as R1 in Step 1 of Production Process PP. R26 hasthe same definition as R6 and R7 in Production Process MO.

Step 1 represents a step of treating compound (PR4-a) with Lawesson'sreagent while heating in 1,4-dioxane to yield a thioamide (PR4-b).

Step 2 represents a step of treating compound (PR4-b) with ethylO-trifluoromethanesulfonylhydroxyacetate, triphenylphosphine andtriethylamine to yield compound (PR4-c).

Step 3 represents a step of reacting compound (PR4-c) with sodiumtriacetoxyborohydride in 1,2-dichloroethane in the presence of aceticacid for reduction of the enamine to yield compound (PR4-d).

Step 4 represents a step of converting compound (PR4-d) to a carboxylicacid derivative (PR4-e) under appropriate conditions such thatsubstituent R26 is not affected. Generally, it is treated with aqueoussodium hydroxide or aqueous lithium hydroxide in an alcohol or analcohol-tetrahydrofuran mixed solvent for alkali hydrolysis to yieldcompound (PR4-e).

Step 5 represents a step of treating compound (PR4-e) with di-tert-butyldicarbonate in tert-butanol in the presence of dimethylaminopyridine toyield the tert-butylesterified compound (PR4-f).

Compounds (PR4-c), (PR4-d) and (PR4-f) obtained in this Scheme (PR-4)may be converted to the final target compounds by Production Process A.

Scheme PR-5 is an exemplary production scheme whereby the —N—Y1-Y2-Y3(—N) portion obtained by cyclization in Step 1 of Production Process MOmay undergo additional structural conversion. In the formulas, R1 hasthe same definition as R1 in Step 1 of Production Process PP. R27 hasthe same definition as R6 and R7 in Production Process MO.

Step 1 represents a step of treating compound (PR5-a) with a catalyticamount of rhodium (II) acetate dimer and the known reagent diethyldiazomalonate while heating in toluene, to yield compound (PR5-b).

Step 2 represents a step of treating compound (PR5-b) with equivalentsof sodium ethoxide and ethyl acrylate while heating in ethanol to yieldthe cyclized compound (PR5-c).

Step 3 represents a step of treating compound (PR5-c) with 5 Nhydrochloric acid while heating in ethanol to yield compound (PR5-d)having the methoxymethyl protecting group removed.

Step 4 represents a step of converting compound (PR5-d) to compound(PR5-e) having a newly introduced substituent R27. Compound (PR5-e) maybe obtained by treatment in the same manner as for introduction of R7 inStep 3 of Production Process MO.

Step 5 represents a step of treating compound (PR5-e) with1,2-bis(trimethylsiloxy)ethane and triethylsilyltriflate indichloromethane to yield compound (PR5-f), wherein the acetyl carbonylof compound (PR5-e) is ketal-protected.

Step 6 represents a step of reducing the lactam carbonyl of compound(PR5-f) for conversion to methylene. Compound (PR5-f) may be reactedwith carbonylhydridotris(triphenylphosphine)rhodium(I) anddiphenylsilane in an appropriate solvent such as tetrahydrofuran toyield compound (PR5-g).

Step 7 represents a step of reacting compound (PR5-g) in 5% hydrochloricacid-tetrahydrofuran to yield the ketal-deprotected compound (PR5-h).

Compounds (PR5-d), (PR5-e) and (PR5-h) obtained in this Scheme PR-5 maybe converted to the final target compounds by Production Process A.

This Production Process PS is an exemplary synthetic method for apiperidine derivative. In the formulas, R1 has the same definition as R1in Step 1 of Production Process PP. R28 and R30 have the samedefinitions as R6 and R7 in Production Process MO.

Step 1 represents a step of reacting compound (PS-a) with formaldehydeto produce an imine, and then subjecting it to hetero Diels-Alderreaction with a diene having an enol ether structure to form anoxopiperidine ring. Preferably, Compound (PS-a) is reacted with 37%formalin in dichloromethane in the presence of magnesium sulfate toproduce an imine, and the reaction mixture is filtered with celite.After adding 2-trimethylsilyloxy-1,3-butadiene and toluene to thefiltrate and cooling to −70° C., a 1 M hexane solution ofdiethylaluminum chloride is added dropwise and the temperature israised. After completion of the reaction, the mixture is replaced with atetrahydrofuran solution and is treated with 1 N hydrochloric acid toyield compound (PS-b) having the silylenol ether converted to a ketone.

Step 2 represents a step of treating compound (PS-b) withp-toluenesulfonylmethyl isocyanide (TosMIC) indimethoxyethane-tert-butanol in the presence of potassium tert-butoxide,to yield compound (PS-c) having oxo converted to cyano.

Step 3 represents a step of reacting the carbonyl group of compound(PS-b) with any of various organometallic reagents to yield atert-alcohol (PS-d) having an added substituent R29. For example,compound (PS-b) may be reacted with methylmagnesium bromide in diethylether to yield compound (PS-d) having an added methyl group. R29represents alkyl, alkenyl or alkynyl.

Step 4 represents a step of treating compound (PS-b) with a reducingagent for conversion to an alcohol compound (PS-e). Various reducingagents may be used, and treatment with sodium borohydride in amethanol-dichloromethane mixed solvent is preferred to yield compound(PS-e).

Step 5 represents a step of treating compound (PS-e) in the same manneras Step 1 of Scheme PR-1 of Production Process PR-1 to yield compound(PS-f) having a newly introduced substituent R30 at the hydroxyl group.Substituent R30 has the same definition as R6 and R7 in ProductionProcess MO.

Step 6 represents a step of Horner-Emmons reaction at the carbonyl groupof compound (PS-b) to yield the carbon-carbon bond formed unsaturatedester (PS-g). After treating a tert-butyl diethylphosphonoacetate withsodium hydride in 1,2-dimethoxyethane, compound (PS-b) dissolved in1,2-dimethoxyethane is added to yield Compound (PS-g).

Step 7 represents a step of 1,4-reduction of the unsaturated ester.Compound (PS-g) may be treated with sodium borohydride in adichloromethane-methanol mixed solvent in the presence of a catalyticamount of nickel (II) chloride.6 hydrate, or reacted with magnesium inmethanol for selective 1,4-reduction of the unsaturated ester to yieldcompound (PS-h).

A piperidine derivative may also be synthesized by the following Steps 8to 10.

Step 8 represents a step of treating compound (PS-i) in the same manneras Step 1 to yield compound (PS-j), with simultaneous formation of anoxopiperidine ring and deprotection of the methoxymethyl group servingas the phenolic hydroxyl group-protecting group.

Step 9 represents a step of treating compound (PS-j) in the same manneras for introduction of R7 in Step 3 of Production Process MO, to yieldcompound (PS-k) substituted with substituent R28.

Step 10 represents a step of selectively protecting the carbonyl groupof the acetophenone of compound (PS-k). After adding compound (PS-k) totetrahydrofuran, adding triethylamine and cooling to −70° C., themixture is treated with tert-butyldimethylsilyltrifluoromethanesulfonate. The state of the reaction is periodicallyexamined by thin-layer column chromatography, and the temperature isgradually raised if necessary. Water may be added at low temperature tostop the reaction to yield compound (PS-m).

Finally, compound (PS-m) may be treated in the same manner as in Steps2, 3 and 4. Alternatively, it may be converted directly to an acylbromide according to Production Process A for conversion to the finaltarget compound.

Compounds (PS-b), (PS-c), (PS-d), (PS-e), (PS-f), (PS-g), (PS-h), (PS-j)and (PS-k) obtained in this Production Process may be converted to thefinal target compounds by Production Process A.

<Production Process AN>

This scheme is an exemplary synthesis for an aniline derivative. In theformulas, R1 has the same definition as in Step 1 of Production ProcessPP. R31, R32 and R33 have the same definitions as R6 and R7 inProduction Process MO.

Step 1 represents a step of introducing one or two substituents R31 atthe amino group of compound (AN1-a). Compound (AN1-a) may be treated inapproximately the same manner as for introduction of R7 at the hydroxylgroup in Step 3 of Production Process MO to yield compounds (AN1-b) and(AN1-c). When R31 is bonded to the aniline amino group as simple alkyland not via acyl or sulfonyl (when R31-I or R31-Br is used as thereagent, etc.), a prolonged reaction with heating may be necessary tointroduce the substituent R31. Incidentally, compounds (AN1-b) and(AN1-c) may be easily separated and purified by silica gel columnchromatography.

Step 2 represents a step of treating compound (AN1-b) in the same manneras Step 1 to yield compound (AN1-d) having a newly introducedsubstituent R32.

Step 3 represents a step of treating compounds (AN1-c) and (AN1-d) inthe same manner as Step 2 of Production Process MO to yield therespective compounds (AN1-e) and (AN1-f).

Step 4 represents a step of treating compounds (AN1-e) and (AN1-f) inthe same manner as for introduction of R7 in Step 3 of ProductionProcess MO to yield the respective compounds (AN1-g) and (AN1-h).

Step 5 represents a step of using compound (AN1-i) as the startingmaterial for treatment in the same manner as Step 1 to yield compound(AN1-j) having substituents R31 and R33. Compound (AN1-g) can also beobtained by this method.

Step 6 represents a step of treating compound (AN1-j) in the same manneras Step 2 to yield compound (AN1-h).

Step 7 represents a step of treating compound (AN1-i) in the same manneras the ketalizing reaction of Step 6 in Scheme PR-2, to yield compound(AN1-k).

Step 8 represents a step of reductive amination of compound (AN1-k)using an aldehyde or ketone (represented by R34(C═O)—R35) and a reducingagent to obtain compound (AN1-m).

Compound (AN1-k) may be reacted with sodium cyanoborohydride in amethanol-acetic acid mixed solvent or reacted with sodiumtriacetoxyborohydride in a 1,2-dichloroethane-acetic acid mixed solvent,to directly yield compound (AN1-m) having the ketal protecting groupalso deprotected. Either R34 and R35 may be hydrogen, or R34 and R35 maytogether form a ring.

Step 9 represents a step of reductive amination of compound (AN1-i)without ketal protection, using an aldehyde or ketone (represented byR34-(C═O)—R35) and a reducing agent to yield compound (AN1-m). Reactionwill usually be conducted with sodium triacetoxyborohydride in a1,2-dichloroethane-acetic acid mixed solvent.

Compounds (AN1-b), (AN1-c), (AN1-d), (AN1-e), (AN1-f), (AN1-g), (AN1-h),(AN1-j) and (AN1-m) obtained in this Scheme AN-1 may be converted to thefinal target compounds by Production Process A.

Scheme AN-2 is an exemplary synthetic method for further structuralconversion of the substituents on the aniline nitrogen of theintermediate synthesized in Scheme AN-1. In the formulas, R1 has thesame definition as R1 in Step 1 of Production Process PP. R36 has thesame definition as R6 and R7 in Production Process MO. Either or bothR37 and R38 may form an amide bond with the aniline nitrogen, or thesubstituents may have ester structures. One of the substituents on theaniline nitrogen of the starting material (AN2-a) may be hydrogen.

Step 1 represents a step of treating compound (AN2-a) in the same manneras the ketalizing reaction of Step 6 in Scheme PR-2 of ProductionProcess PR, to yield compound (AN2-b) having the carbonyl groupprotected.

Step 2 represents a step of treating compound (AN2-b) with a reducingagent for conversion of amide to methyleneamino (from —N—CO— to—N—CH2-), or of an ester to an alcohol (from —CO—O— to —CH2-OH, from—O—CO— to —OH). Preferably, compound (AN2-b) is treated with lithiumaluminum hydride in diethyl ether to yield compound (AN2-c).Substituents R39 and R40 are defined as the structures resulting afterthis conversion of R37 and R38.

Step 3 represents a step of treating compound (AN2-c) in the same manneras the ketal deprotection reaction of Step 7 in Scheme PR-2, to yieldcompound (AN2-d).

Step 4 represents a step carried out only when compound (AN2-d) has ahydroxyl group on substituent R39 or R40, and here a new substituent isintroduced at the hydroxyl group to yield compound (AN2-e) by conversionto substituents R41 and R42.

The reaction of this step is conducted in the same manner as Step 1 inScheme PR-1 of Production Process PR. Compounds (AN2-d) and (AN2-e)obtained in this Scheme (AN-2) may be converted to the final targetcompounds by Production Process A.

<Production Process BO>

The following Schemes BO-1, 2, 3 and 4 of Production Process BO aregeneral synthesis methods for benzoxazine derivatives.

In the formulas, R1 has the same definition as R1 in Step 1 ofProduction Process PP. R2 represents hydrogen, optionally substitutedalkyl or the like. R3 represents hydrogen, halogeno, oxo, optionallysubstituted alkyl, optionally substituted alkoxy, optionally substitutedacyl, optionally substituted carboxyl or optionally substitutedcarbamoyl.

Step 1 represents a step of acylation of the amino group. Compound(BO1-b) may be obtained either by reaction with an acyl chloride at roomtemperature in a solvent such as tetrahydrofuran, methylene chloride oracetonitrile in the presence of a base such as pyridine ortriethylamine, or by reaction with an acid anhydride in a pyridinesolution.

Step 2 represents a step of deprotection of the methoxymethyl groupprotecting the alcohol. Compound (BO1-c) may be obtained by reactionwith dilute aqueous hydrochloric acid and 10% aqueous perchloric acid ina solvent such as tetrahydrofuran or acetone at room temperature.

Step 3 represents a step of alkylation of the hydroxyl group and theamino group. Compound (BO1-d) may be obtained by reaction with adihalide, dimesylate or ditosylate in a dimethylformamide solution inthe presence of a base such as potassium carbonate, cesium carbonate orsodium hydride, while heating from room temperature to 150° C.

Step 4 represents a step of deacylation. Compound (BO1-e) may beobtained either by reaction with an aqueous sodium hydroxide solution ina solvent such as methanol, ethanol or tetrahydrofuran, at roomtemperature to the reflux temperature of the solvent, or by reaction inan aqueous hydrochloric acid solution at room temperature to the refluxtemperature of the solvent.

Compounds (BO1-d) and (BO1-e) obtained in this Scheme BO-1 may beconverted to the final target compounds by Production Process A.

In the formulas, R1 has the same definition as R1 in Step 1 ofProduction Process PP. R2 has the same definition as R3 in Scheme BO-1.

Step 1 represents a step of alkylation of the hydroxyl group. Compound(BO2-b) may be obtained by reaction with a dihalide, dimesylate orditosylate in a dimethylformamide solution while heating from roomtemperature to 150° C.

Step 2 represents a step of forming an oxazine ring. Reaction isconducted with a dihalide, dimesylate or ditosylate in adimethylformamide solution in the presence of a base such as potassiumcarbonate, cesium carbonate or sodium hydride, while heating from roomtemperature to 150° C. Reaction is then conducted at room temperature inan ethanol or methanol solution in the presence of a catalytic amount ofpalladium-carbon in a hydrogen atmosphere to yield compound (BO2-c).

Compound (BO2-c) obtained in this Scheme BO-2 may be converted to thefinal target compound by Production Process A.

In the formulas, R1 represents hydrogen, optionally substituted alkyl,optionally substituted cycloalkyl or optionally substituted alkoxy. R2represents hydrogen, optionally substituted alkyl, alkyl having cyano atthe end or a branch, optionally substituted alkoxy, optionallysubstituted arylalkyl, optionally substituted acyl, optionallysubstituted sulfonyl, optionally substituted carbamoyl or optionallysubstituted carboxyl.

Step 1 represents a step of alkylating, acylating, substitutedcarbamoylating or urethanating the amino group, by any of the followingmethods 1 to 4.

1. Compound (BO3-b) may be obtained by reaction with a halide, mesylateor tosylate in a dimethylformamide solution in the presence of a basesuch as potassium carbonate, cesium carbonate or sodium hydride, whileheating from room temperature to 150° C.

2. Compound ((BO3-b) may be obtained either by reaction with an acylchloride, sulfonyl chloride or isocyanate at room temperature in asolvent such as tetrahydrofuran, methylene chloride or acetonitrile, inthe presence of a base such as pyridine or triethylamine, or by reactionwith an acid anhydride in a pyridine solution.

3. Compound ((BO3-b) may be obtained by reaction with ethylN—(1-cyano)iminoformate in methanol or ethanol in the presence of acatalytic amount of 4-dimethylaminopyridine, at room temperature to thereflux temperature of the solvent.

4. Compound (BO3-b) may be obtained by reaction with trimethylorthoformate or triethyl orthoformate in methanol or ethanol in thepresence of a catalytic amount of p-toluenesulfonic acid orcamphorsulfonic acid, ketal protection of the acetyl group andintroduction of different substituents by methods 1 to 3 above, followedby deprotection under acidic conditions.

Compound (BO3-b) obtained in this Scheme BO-3 may be converted to thefinal target compound by Production Process A.

In the formulas, R1 has the same definition as R1 in Step 1 ofProduction Process PP. R2 has the same definition as R3 in Scheme BO-1.R3 has the same definition as R2 in Scheme BO-3.

Step 1 represents a step of alkylation. Compound (BO4-b) may be obtainedby the method described in Tawada, H., Sugiyama, Y., Ikeda, H.,Yamamoto, Y., Meguro, K; Chem. Pharm. Bull., 38 (5), 1238–1245 (1990),or by reaction with allyl bromide, maleic anhydride or the like in asolvent such as methanol, ethanol or toluene in the presence of a basesuch as potassium carbonate, cesium carbonate or sodiumhydrogencarbonate at room temperature to the reflux temperature of thesolvent, followed by reaction in methanol or ethanol in the presence ofa base such as potassium carbonate or triethylamine, at room temperatureto the reflux temperature of the solvent.

Step 2 represents a step of alkylating, acylating, substitutedcarbamoylating or urethanating the amino group. Compound (BO4-c) may beobtained by treatment in the same manner as Step 1 of Scheme BO-3.Compounds (BO4-b) and (BO4-c) obtained in Scheme BO-4 may be convertedto the final target compound by Production Process A.

Production Process BOL is an exemplary synthetic method for abenzoxazole derivative. In the formulas, R1 has the same definition asR1 in Step 1 of Production Process PP. R2 represents hydrogen,optionally substituted alkyl or optionally substituted alkoxy.

Step 1 represents a step of forming an oxazole ring. Compound (BOL-b)may be obtained by reaction with an acid chloride in a solvent such astetrahydrofuran, methylene chloride or acetonitrile in the presence of abase such as triethylamine, followed by reaction with dilute aqueoushydrochloric acid or p-toluenesulfonic acid in a solvent such asethanol, methanol, tetrahydrofuran or methyl ethyl ketone.

The benzoxazoleethanone derivative (BOL-b) obtained in ProductionProcess BOL may be converted to the final compound by Production ProcessA.

<Production Process CA>

Schemes CA-1, 2 and 3 below in Production Process CA are generalsynthesis methods for catechol derivatives.

In the formulas, R1 has the same definition as R1 in Step 1 ofProduction Process PP. R2, R3 and R4 have the same definitions as R6 andR7 in Production Process MO.

Step 1 represents a step of methoxymethylating the hydroxyl group ofcompound (CA1-a). Compound (CA1-b) is obtained by reaction of compound(CA1-a) and sodium hydride in dimethylformamide at room temperature,followed by reaction with methoxymethyl chloride (MOM-Cl).

Step 2 represents a step of introducing a formyl group byortholithiation utilizing the substituent effect of the methoxymethylgroup of compound (CA1-b). The orthoformylated compound (CA1-c) isobtained by treatment of compound (CA1-b) with n-butyllithium in diethylether while cooling on ice in the presence oftetramethylethylenediamine, followed by treatment with a formylatingagent such as dimethylformamide or N-formylmorpholine.

Step 3 represents a step of brominating the para-position relative tothe methoxymethyl group of compound (CA1-c). Compound (CA1-d) isobtained by reaction of compound (CA1-c) with bromine in methanol atroom temperature, and removal of the methoxymethyl group by the hydrogenbromide generated in the system.

Step 4 represents a step of introducing any of various substituents atthe hydroxyl group of compound (CA1-d). Compound (CA1-e) is obtained bythe same method as for introduction of R7 in Step 3 of ProductionProcess MO.

Step 5 represents a step of oxidative conversion of the formyl group toa hydroxyl group. Compound (CA1-f) is obtained by reacting compound(CA1-e) with m-chloroperbenzoic acid in dichloromethane at roomtemperature or with heating, and then hydrolyzing the purified esterusing potassium carbonate in methanol.

Step 6 represents a step of obtaining R3 introduced compound (CA1-g) bythe same method as in Step 4 of Scheme CA-1.

Step 7 represents a step of conversion to substituent R4 when R2 is ahydroxyl-protecting group. Compound (CA1-h) is obtained in the samemanner as the continuous treatment in Steps 2 and 3 of ProductionProcess MO.

Compounds (CA1-g) and (CA1-h) obtained in this Scheme CA-1 may beconverted to the final target compound by Production Process A.

Scheme CA-2 is an exemplary synthetic method for a cyclic catecholderivative. In the formulas, R1 has the same definition as R1 in Step 1of Production Process PP. R2 and R4 have the same definitions as R6 andR7 in Production Process MO.

Step 8 represents a step of conversion to a catechol when R2 is aneliminable hydroxyl-protecting group. When R2 is methoxymethyl, a diol(catechol) (CA2-a) is obtained by treating compound (CA1-f) with 6 Nhydrochloric acid.

Step 9 represents a step of cyclizing the catechol by alkylation.Compound (CA2-a) is reacted with a 1,2-dibromoethyl derivative in asolvent such as dimethylformamide, acetonitrile or acetone in thepresence of a base such as potassium carbonate, cesium carbonate orsodium hydride, to yield a fused dioxane ring (CA2-b). Compound (CA2-a)may also be treated with acetone in the presence of phosphoruspentaoxide to yield a 5-membered cyclic product (CA2-b) as an acetonide.

Compound (CA2-b) obtained in this Scheme CA-2 may be converted to thefinal target compound by Production Process A.

Scheme CA-3 is an exemplary synthetic method for a disubstitutedcatechol derivative. In the formulas, R5 and R6 have the samedefinitions as R6 and R7 in Production Process MO.

Step 10 represents a step of obtaining compound (CA3-b) by the samemethod as in Step 4 of Scheme CA-1 using the catechol (CA3-a) as thestarting material.

Step 11 represents a step of treating compound (CA3-b) by the samemethod as in Step 3 of Scheme CA-1 to yield compound (CA3-c) which isselectively brominated at the para-position relative to thenon-substituted hydroxyl group.

Step 12 represents a step of obtaining R6 introduced compound (CA3-d) bythe same method as in Step 4 of Scheme CA-1.

Compound (CA3-d) obtained by Scheme CA-3 may be converted to the finaltarget compound by Production Process A.

<Production Process CO>

Schemes CO-1, CO-2, CO-3, CO-4, CO-5, CO-6, CO-7, CO-8 and CO-9 inProduction Process CO are general synthesis methods for phenol andphenoxy derivatives.

In the formulas of Scheme CO-1, R1 and R2 have the same definition as R1in Step 1 of Production Process PP. R3 has the same definition as R6 andR7 in Production Process MO.

Step 1 represents a step of Friedel-Crafts acylation. Compound (CO-b) isobtained by reaction with acetyl chloride in methylene chloride ortoluene in the presence of a Lewis acid such as aluminum chloride, zincchloride or tin (II) chloride, at −70° C. to room temperature.

Step 2 represents a step of alkylation, carbonation, sulfonation or thelike.

1. Compound (CO1-c) may be obtained by reaction with a halide, mesylateor tosylate in a dimethylformamide solution in the presence of a basesuch as potassium carbonate, cesium carbonate or sodium hydride, whileheating from room temperature to 150° C.

2. Compound (CO1-c) may be obtained either by reaction with an acylchloride, sulfonyl chloride or isocyanate in a solvent such astetrahydrofuran, methylene chloride or acetonitrile in the presence of abase such as pyridine or triethylamine, at −15° C. to room temperature,or by reaction with an acid anhydride in a pyridine solution.

3. Compound (CO1-c) may also be obtained by reaction with phenylchloroformate in a solvent such as tetrahydrofuran, methylene chlorideor acetonitrile in the presence of a base such as pyridine ortriethylamine, followed by reaction with an amine.

Compounds (CO1-b) and (CO1-c) obtained in this Scheme CO-1 may beconverted to the final target compounds by Production Process A.Compound (CO1-a) may also be used in the conversion of compound (A4-c)in Scheme A-4 of Production Process A.

Scheme CO-2 is an exemplary synthetic method for an aromatic-substitutedbenzene derivative. In the formulas, R1 has the same definition as R1 inStep 1 of Production Process PP. R2 has the same definition as R6 and R7in Production Process Mo. R3 represents an aromatic ring.

Step 1 represents a step of introducing an aromatic substituent usingthe Stille coupling method. Compound (CO2-b) is obtained by reactionwith aromatic-substituted tributyltin in a solvent such as toluene orxylene under a nitrogen atmosphere in the presence of a catalytic amountof tetrakis(triphenylphosphine)palladium, at the reflux temperature ofthe solvent.

Compound (CO2-b) obtained in this Scheme CO-2 may be converted to thefinal target compound by Production Process A.

Scheme CO-3 is an exemplary synthetic method for a benzylaminederivative. In the formulas, R1 and R3 have the same definition as R1 inStep 1 of Production Process PP. R2 and R2′ have the same definitions asR6 and R7 in Production Process MO. R4 and R5 have the same definitionas R2 in Scheme BO-3. R4 and R5 may also form a ring together. Xrepresents hydroxyl or sulfonate.

Step 1 represents a step of introducing an alkyl halide. Compound(CO3-b) is obtained by reaction with sodium borohydride in methanol orethanol, followed by reaction with methanesulfonyl chloride or the likein dimethylformamide, in the presence of a base such as pyridine ortriethylamine.

Step 2 represents a step of amination.

1. Compound (CO3-c) may be obtained by reaction with an amine inmethanol, ethanol, acetonitrile or tetrahydrofuran.

2. Compound (CO3-c) may be obtained by reaction with an amine indimethylformamide in the presence of a base such as potassium carbonateor sodium hydride.

3. When X is hydroxyl, compound (CO3-c) may be obtained by reaction withdiphenylphosphoryl azide in toluene in the presence of a base such as1,8-diazabicyclo[5.4.0]undec-7-ene to yield an azide, followed byreaction with a trialkylphosphine or triphenylphosphine intetrahydrofuran-water.

Step 3 represents a step of converting R2 to substituent R2′ when R2 isa hydroxyl-protecting group. Compound (CO3-d) is obtained in the samemanner as the continuous treatment in Steps 2 and 3 of ProductionProcess MO.

Compounds (CO3-c) and (CO3-d) obtained in this Scheme CO-3 may beconverted to the final target compounds by Production Process A.

Scheme CO-4 is an exemplary synthetic method for phenol and phenoxyderivatives by Wittig reaction. In the formulas, R1 has the samedefinition as R1 in Production Process PP. R2 and R2′ have the samedefinitions as R6 and R7 in Production Process MO. R3 representshydrogen or lower alkyl. R4 represents optionally substituted alkyl,optionally substituted carboxyl, cyano or the like.

Step 1 represents a step of alkylation utilizing Wittig reaction.Reaction is conducted with a phosphorane derivative in methylenechloride or tetrahydrofuran. Alternatively, compound (CO4-b) may beobtained by reaction with a phosphonium salt or phosphonate intetrahydrofuran or dimethylformamide in the presence of a base such aspotassium tert-butoxide or sodium hydride.

Step 2 represents a step of reducing the olefin. Compound (CO4-c) may beobtained by accomplishing reduction by reaction in ethyl acetate,tetrahydrofuran or methanol under a hydrogen atmosphere in the presenceof palladium-carbon, or by reaction with magnesium in methanol.

Step 3 represents a step of conversion to substituent R2′ when R2 is ahydroxyl-protecting group. Compound (CO4-d) is obtained in the samemanner as the continuous treatment in Steps 2 and 3 of ProductionProcess MO.

Compounds (CO4-b), (CO4-c) and (CO4-d) obtained in this Scheme CO-4 maybe converted to the final target compounds by Production Process A.

Scheme CO-5 is an exemplary synthetic method for phenol and phenoxyderivatives utilizing Friedel-Crafts reaction. In the formulas, R1 hasthe same definition as R1 in Step 1 of Production Process PP. R2represents hydrogen, optionally substituted alkyl or optionallysubstituted cycloalkyl. R3 has the same definition as R6 and R7 inProduction Process MO.

Step 1 represents a step of bromination at the para-position of phenyl.Reaction may be conducted either with bromine in methanol or ethanol orwith N-bromosuccinimide in acetonitrile to yield Compound (CO5-a).

Step 2 represents a step of alkylation by Friedel-Crafts reaction.Compound (CO5-b) is obtained by reaction with alkyl mesylate in benzeneor dichloroethane in the presence of scandium triflate, by the methoddescribed in H. Katsuki et al., Synthesis 603 (1999).

Step 3 represents a step of introducing a substituent R3 at the hydroxylgroup. Compound (CO5-c) is obtained by treatment in the same manner asfor introduction of R7 in Step 3 of Production Process MO.

Compounds (CO5-b) and (CO5-c) obtained in Scheme CO-5 may be convertedto the final target compounds by Production Process A.

Scheme CO-6 is an exemplary synthetic method for carboxylic acidderivatives and benzyl alcohol derivatives. In the formulas, R1 has thesame definition as R1 in Step 1 of Production Process PP. R2 representsoptionally substituted alkyl and R3 and R4 have the same definitions asR6 and R7 in Production Process MO.

Step 1 represents a step of introducing a carboxyl group byortholithiation utilizing the substituent effect of the methoxymethylgroup of compound (CA1-b). Compound (CO6-a) is obtained by treatingcompound (CA1-b) with n-butyllithium in diethyl ether in the presence oftetramethylethylenediamine while cooling on ice, and then reacting itwith an alkyl dicarbonate.

Step 2 represents a step of deprotection of the methoxymethyl groupserving as the alcohol-protecting group. Compound (CO6-b) is obtained byreaction with dilute aqueous hydrochloric acid and 10% aqueousperchloric acid in tetrahydrofuran or acetone at room temperature.

Step 3 represents a step of introducing a substituent R3 at the hydroxylgroup. Compound (CO6-c) is obtained by treatment in the same manner asfor introduction of R7 in Step 3 of Production Process MO.

Step 4 represents a step of reduction and alkylation of the carboxylgroup. Compound (CO6-d) is obtained by reaction with lithium aluminumhydride in diethyl ether or tetrahydrofuran while cooling on ice,followed by the same method as in Step 3.

Compounds (CO6-b), (CO6-c) and (CO6-d) obtained in this Scheme CO-6 maybe converted to the final target compounds by Production Process A.

Scheme CO-7 is an exemplary synthetic method for phenethyl alcoholderivatives, phenylacetic acid derivatives and benzofuran derivatives.In the formulas, R1 has the same definition as R1 in Step 1 ofProduction Process PP. R2 and R3 have the same definitions as R6 and R7in Production Process MO. R4 and R5 represent optionally substitutedalkyl.

Step 1 represents a step of introducing a hydroxyl group by Wittigreaction followed by hydroboration reaction. The reaction is conductedwith methyltriphenylphosphonium bromide in tetrahydrofuran in thepresence of potassium tert-butoxide. Reaction is then conducted withborane-tetrahydrofuran in tetrahydrofuran and with 30% aqueous hydrogenperoxide to yield compound (CO7-a).

Step 2 represents a step of introducing a substituent R3 at the hydroxylgroup. Compound (CO7-b) is obtained by treatment in the same manner asfor introduction of R7 in Step 3 of Production Process MO.

Step 3 represents a step of carbon-carbon bond formation. Compound(CO7-c) is obtained by reaction with methyl methylthiomethyl sulfoxidein tetrahydrofuran in the presence of Triton B, at the refluxtemperature of the solvent, followed by reaction with dilute aqueoushydrochloric acid in methanol or ethanol.

Step 4 represents a step of oxidation. Compound (CO7-c) is obtained bythe method described in Mangzho Zhao et al., Tetrahedron Lett. 39, 5323(1998) or the method described in Ryoji Noyori et al., J. Am. Chem.Soc., 119, 12386 (1997).

Step 5 represents a step of forming a furan ring when R2 is hydrogen.Compound (CO7-d) is obtained by reaction with a bromoacetic acid esterin dimethylformamide in the presence of potassium carbonate, at thereflux temperature of the solvent.

Compounds (CO7-a), (CO7-b), (CO7-c) and (CO7-d) obtained in this SchemeCO-7 may be converted to the final target compounds by ProductionProcess A.

Scheme CO-8 is an exemplary synthetic method for 2,3-dihydrobenzofuranderivatives or 2,3-dihydrobenzothiophene derivatives. In the formulas,R1 has the same definition as R1 in Step 1 of Production Process PP. R2and R3 represent hydrogen, optionally substituted alkyl or optionallysubstituted alkoxy.

Step 1 represents a step of alkylation of the hydroxyl group. Compound(CO8-b) is obtained by reaction with an allyl halide, allyl mesylate orallyl tosylate in a solvent such as dimethylformamide, acetonitrile oracetone, in the presence of sodium iodide and in the presence of a basesuch as potassium carbonate, cesium carbonate or sodium hydride,according to the method described in J. M. Janusz et al., J. Med. Chem.41, 1112 (1998).

Step 2 represents a step of forming a furan or thiophene ring. Compound(CO8-c) is obtained by the method described in J. M. Janusz et al., J.Med. Chem. 41, 1112 (1998), or by reaction at 210° C. in magnesiumchloride.

Step 3 represents a step of Friedel-Craft acylation. Compound (CO8-d) isobtained by reaction with acetyl chloride in methylene chloride ortoluene in the presence of a Lewis acid such as aluminum chloride, zincchloride or tin (II) chloride, at −70° C. to room temperature.

Step 4 represents a step of bromination by reaction with bromine inmethanol or ethanol. Alternatively, compounds (CO8-e) and (CO8-g) areobtained by reaction with N-bromosuccinimide in acetonitrile ordimethylformamide.

Step 5 represents a step of forming a furan or thiophene ring. Compound(CO8-g) is obtained by reaction with sodium borohydride at 75° C. indimethylacetamide in the presence of cyclopentadienyldichlorotitanium,by the method described in J. Schwaltz et al., J. Org. Chem. 59, 940(1994).

Compounds (CO8-d) and (CO8-g) obtained in this Scheme CO-8 may beconverted to the final target compounds by Production Process A.

Scheme CO-9 is an exemplary synthetic method for carboxylic acidderivatives. In the formulas, R1, R2, R3 and R4 represent hydrogen oroptionally substituted alkyl.

Step 1 represents a step of alkylation. Compound (CO9-b) is obtained byreaction with an alkyl halide, mesylate or tosylate in tetrahydrofuranor dimethylformamide, in the presence of potassium tert-butoxide orsodium hydride.

Step 2 represents a step of reduction. Compound (CO9-c) is obtained byreaction with diisobutylaluminum hydride in tetrahydrofuran.

Step 3 represents a step of carbon-carbon bond formation utilizingWittig reaction. The reaction is conducted with a phosphorane derivativein methylene chloride or tetrahydrofuran. Alternatively, compound(CO9-d) is obtained by reaction with either a phosphonium salt orphosphonate in tetrahydrofuran or dimethylformamide in the presence of abase such as potassium tert-butoxide or sodium hydride.

Compounds (CO9-b) and (CO9-d) obtained in this Scheme CO-9 may beconverted to the final target compounds by Production Process A.

Representative production processes for compounds according to theinvention and salts thereof have been described above, but the startingcompounds and reagents used for production of the compounds of theinvention may also form salts or hydrates, and these are notparticularly restricted so long as the reaction is not inhibited. Whencompound (I) of the invention is obtained as a free compound, a commonmethod may be used to convert it to a salt which compound (I) may form.The different isomers (for example, geometric isomers, optical isomersbased on asymmetric carbon, stereoisomers, tautomers or the like)obtained for compound (I) according to the invention may be purified andisolated using common separation means such as recrystallization,diastereomer salt methods, enzymatic resolution methods andchromatography methods (for example, thin-layer chromatography, columnchromatography, gas chromatography, etc.).

In certain embodiments, compounds of the invention represented byformula (I) and salts thereof exhibit excellent thrombin receptorantagonism and especially selective antagonism against PAR1 thrombinreceptors. In certain other embodiments, compounds of the invention andtheir salts also exhibit excellent inhibition against plateletaggregation and smooth muscle cell proliferation, with high oralefficacy. In yet other embodiments, compounds of the invention and saltsthereof can therefore inhibit the cellular response to thrombin whichincludes platelet aggregation, without inhibiting the catalytic activityof thrombin which converts fibrinogen to fibrin, and can also inhibitvascular smooth muscle proliferation occurring as a result of damage tovascular walls by coronary angioplasty and the like, through selectiveinhibition of PAR1.

Thus, in certain embodiments, compounds of the invention and saltsthereof may be used to obtain pharmaceutical compositions (formulations)as (i) thrombin receptor antagonists (especially PAR1 thrombin receptorantagonists), (ii) platelet aggregation inhibitors, (iii) smooth musclecell proliferation inhibitors, (iv) endothelial cell, fibroblast,nephrocyte, osteosarcoma cell, muscle cell, cancer cell and/or glia cellproliferation inhibitors and (v) therapeutic or prophylactic agents forthrombosis, vascular restenosis, deep venous thrombosis, pulmonaryembolism, cerebral infarction, heart diseases, disseminatedintravascular coagulation, hypertension, inflammatory diseases,rheumatism, asthma, glomerulonephritis, osteoporosis, neurologicaldiseases and/or malignant tumors.

In certain embodiments, compounds of the invention and their salts maybe administered for treatment of patients suffering from diseasesassociated with thrombin receptors, and for treatment of patientssuffering from proliferative diseases of, for example, endothelial cell,fibroblast, nephrocyte, osteosarcoma cell, muscle cell, cancer celland/or glia cell.

A compound of the invention represented by formula (I) above, a saltthereof or a hydrate of the foregoing may be formulated by aconventional method. Exemplary dosage forms include tablets, powders,fine particles, granules, coated tablets, capsules, syrups, lozenges,inhalants, suppositories, injections, ointments, eye salves, eye drops,nasal drops, ear drops, paps, lotions and the like. Formulations may beprepared with any commonly used excipients, binders, disintegrators,lubricants, coloring agents, corrective coatings, and if necessary,stabilizers, emulsifiers, absorbefacients, surfactants, pH adjustors,preservatives, antioxidants, or the like, in combination with variouscomponents that are ordinarily used as materials for pharmaceuticalformulations.

For example, such components include (1) animal and vegetable oils suchas soybean oil, beef tallow and synthetic glycerides; (2) hydrocarbonssuch as liquid paraffin, squalane and solid paraffin; (3) ester oilssuch as octyldodecyl myristate and isopropyl myristate; (4) higheralcohols such as cetostearyl alcohol and behenyl alcohol; (5) siliconeresins; (6) silicone oils; (7) surfactants such as polyoxyethylene fattyacid esters, sorbitan fatty acid esters, glycerin fatty acid esters,polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenatedcastor oil and polyoxyethylene/polyoxypropylene block copolymer; (8)water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid,carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone andmethylcellulose; (9) lower alcohols such as ethanol and isopropanol;(10) polyhydric alcohols such as glycerin, propylene glycol, dipropyleneglycol and sorbitol; (11) sugars such as glucose and sucrose; (12)inorganic powders such as silicic anhydride, magnesium aluminum silicateand aluminum silicate; (13) purified water, and the like.

Examples of (1) excipients which may be used include lactose, cornstarch, white soft sugar, glucose, mannitol, sorbit, crystallinecellulose and silicon dioxide; examples of (2) binders which may be usedinclude polyvinyl alcohol, polyvinyl ether, methylcellulose,ethylcellulose, gum arabic, tragacanth, gelatin, shellac,hydroxypropylcellulose, hydroxypropylmethylcellulose,polyvinylpyrrolidone, polypropylene glycol/polyoxyethylene blockpolymer, meglumine, calcium citrate, dextrin and pectin; examples of (3)disintegrators which may be used include starch, agar, gelatin powder,crystalline cellulose, calcium carbonate, sodium hydrogencarbonate,calcium citrate, dextrin, pectin and calcium carboxymethylcellulose;examples of (4) lubricants which may be used include magnesium stearate,talc, polyethylene glycol, silica and hydrogenated vegetable oils;examples of (5) coloring agents which may be used include any of thoseapproved for addition to drugs; examples of (6) corrective coatingswhich may be used include cocoa powder, menthol, aromatic powders,mentha oil, borneol and powdered cinnamon; and examples of (7)antioxidants which may be used include those approved for addition todrugs, such as ascorbic acid, α-tocopherol and the like.

(i) An oral formulation may be prepared by combining a compound of theinvention or its salt with an excipient, if necessary adding a binder,disintegrator, lubricant, coloring agent, corrective coating or thelike, and forming a powder, fine particles, granules, tablets, coatedtablets, capsules, etc. by a common method. (ii) Tablets or granulesmay, of course, also be coated with a sugar coating, gelatin coating orother type of suitable coating if necessary. (iii) In the case of aliquid formulation such as syrup, injection, eye drops or the like, acommon method may be used for formulation with a pH adjustor,solubilizer, isotonizing agent or the like, as well as a solubilizingaid, stabilizer, buffering agent, suspending agent, antioxidant, etc. ifnecessary. In the case of a liquid formulation, it may also belyophilized, and an injection may be administered intravenously,subcutaneously or intramuscularly. As preferred examples of suspendingagents there may be mentioned methylcellulose, polysorbate 80,hydroxyethylcellulose, gum arabic, tragacanth powder, sodiumcarboxymethylcellulose, polyoxyethylene sorbitan monolaurate and thelike; as preferred examples of solubilizing aids there may be mentionedpolyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide,polyoxyethylene sorbitan monolaurate and the like; as preferred examplesof stabilizing agents there may be mentioned sodium sulfite, sodiummetasulfite, ether and the like; and as preferred examples ofpreservatives there may be mentioned methyl p-oxybenzoate, ethylp-oxybenzoate, sorbic acid, phenol, cresol, chlorocresol, and the like.(iv) There are no particular restrictions on the method of preparing anexternal application, and any common method may be employed. The basematerials used may be any raw materials commonly employed in drugs,quasi drugs, cosmetics and the like, and as examples there may bementioned raw materials such as animal and vegetable oils, mineral oils,ester oils, waxes, higher alcohols, fatty acids, silicone oils,surfactants, phospholipids, alcohols, polyhydric alcohols, water-solublepolymers, clay minerals, purified water and the like, with addition ofpH adjustors, antioxidants, chelating agents, antiseptics andfungicides, coloring agents, aromas and the like if necessary. Also,there may be included differentiation-inducing components, or othercomponents such as circulation promoters, microbicides, antiphlogisticagents, cell activators, vitamins, amino acids, humectants, keratolyticagents and the like, as necessary.

The dosage of a drug according to the invention will differ depending onthe patient's severity of symptoms, age, gender and body weight, thedosage form and type of salt, drug sensitivity, the specific type ofdisease, etc. In certain embodiment, the dosage ranges from about 30 μgto 1000 mg, preferably from 100 μg to 500 mg and more preferably from100 μg to 100 mg per day for adults in the case of oral administrationor about 1–3000 μg/kg and preferably 3–1000 μg/kg per day for adults inthe case of injection, administered once or divided over several times aday.

EXAMPLES

Preferred embodiments of the compounds of the invention represented byformula (I) above and salts thereof will now be explained, with theunderstanding that the following examples and test examples are onlyrepresentative and are not intended to be restrictive on the compoundsof the invention or their salts in any way. It will be apparent to thoseskilled in the art that the present invention can be carried out withvarious modifications added beyond these examples, and suchmodifications are also encompassed within the claims of the presentspecification.

Example 1

1-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

(Step 1) 3-Ethylpentyl methanesulfonate

After adding triethyl phosphonoacetate (22.6 g, 101 mmol) dropwise to asolution of 60% sodium hydride (3.8 g, 95 mmol) in anhydroustetrahydrofuran (200 ml) while cooling on ice, the mixture was stirredfor 30 minutes at the same temperature. Next, 3-pentanone (8.53 g, 99.0mmol) was slowly added dropwise, and the mixture was stirred at roomtemperature for 20 hours. After diluting the reaction mixture withdiethyl ether, it was washed with water and brine. The organic layer wasdried over anhydrous sodium sulfate prior to distillation under reducedpressure to yield a crude product of 3-ethyl-2-pentenoate (22.7 g) as alight yellow oil.

A mixture of ethyl 3-ethyl-2-pentenoate (5.0 g, 32 mmol) and 10%palladium-carbon (1.0 g) in ethanol (25 ml)-ethyl acetate (25 ml) wasstirred at room temperature and normal pressure for 20 hours under ahydrogen stream. After filtering the reaction mixture through celite,the filtrate was distilled off under reduced pressure to yield a crudeproduct of ethyl 3-pentanoate (4.15 g) as a light yellow oil.

A solution of the ethyl 3-pentanoate (4.15 g) in anhydroustetrahydrofuran (50 ml) was slowly added dropwise to a suspension oflithium aluminum hydride (2.1 g, 53 mmol) in anhydrous tetrahydrofuran(40 ml) while cooling on ice, and the mixture was stirred at the sametemperature for 1 hour. After diluting the reaction mixture with diethylether, water (6 ml) was slowly added and stirring was continued for 18hours. After filtering the reaction mixture through celite, the filtratewas distilled off under reduced pressure to yield a crude product of3-ethyl-1-pentanol (2.9 g) as a light yellow oil.

Triethylamine (2.4 ml, 17 mmol) was added dropwise to a solution of the3-ethyl-1-pentanol (1.0 g, 8.6 mmol) and methanesulfonyl chloride (0.8ml, 10 mmol) in dichloromethane (20 ml) while cooling on ice, and themixture was stirred for 2 hours. After diluting the reaction mixturewith diethyl ether, it was washed with water and brine, and the organiclayer was dried over anhydrous sodium sulfate prior to distillationunder reduced pressure. The residue was purified by silica gel columnchromatography (solvent: n-hexane-ethyl acetate) to yield the titlecompound (1.38 g) as a colorless oil.

1H-NMR (400 MHz, CDCl3): 0.86 (6H, t, J=7.2 Hz), 1.27–1.41 (5H, m),1.64–1.73 (2H, m), 3.00 (3H, s), 4.24 (2H, t, J=6.8 Hz).

(Step 2) 1-(3-Ethylpentyl)-2-nitro-1H-imidazole

A solution of 2-nitro-1H-imidazole potassium salt (300 mg, 2.0 mmol),3-ethylpentyl methanesulfonate (463 mg, 2.4 mmol) and 18-crown-6 (1.1 g,4.2 mmol) in acetonitrile (10 ml) was heated at 80° C. for 6 hours.After cooling to room temperature, ethyl acetate and water were addedand the organic layer was separated off. After washing with water andbrine, drying was performed with anhydrous sodium sulfate and thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel column chromatography (solvent: n-hexane-ethylacetate) to yield the title compound (370 mg) as a colorless oil.

1H-NMR (CDCl3): 0.88 (6H, t, J=7.2 Hz), 1.22–1.42 (5H, m), 1.67–1.82(2H, m), 4.36–4.44 (2H, m), 7.08 (1H, s), 7.14 (1H, s).

Example 1: Final Step

A solution of the 1-(3-ethylpentyl)-2-nitro-1H-imidazole (370 mg) and10% palladium-carbon (200 mg) in an ethanol (5 ml)-ethyl acetate (5 ml)mixture was stirred at room temperature and normal pressure for 20 hoursunder a hydrogen stream. After filtering the reaction mixture throughcelite, it was washed with ethyl acetate-methanol. The filtrate wasdistilled off under reduced pressure to yield a crude product of1-(3-ethylpentyl)-1H-2-imidazoleamine (305 mg) as a light yellow solid.A solution of the 1-(3-ethylpentyl)-1H-2-imidazoleamine (305 mg, 1.68mmol) and 2-bromo-1-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1-ethanone (660mg, 2.02 mmol) in methanol (20 ml) was heated at 60° C. for 3 hours. Thereaction mixture was distilled under reduced pressure, and the obtainedcrude product was recrystallized from ethyl acetate. After washing thecrystals with diethyl ether, they were dried to yield the targetcompound (700 mg) as a colorless amorphous solid.

1H-NMR (DMSO-d6) δ:

0.82 (6H, t, J=7.6 Hz), 1.13–1.37 (5H, m), 1.41 (18H, m), 1.54–1.63 (2H,m), 3.82–3.92 (2H, m), 5.58 (2H, brs), 6.92 (1H, d, J=2.4 Hz), 7.14 (1H,d, J=2.4 Hz), 7.67–7.81 (4H, m).

The compounds of the following examples were synthesized by the samemethod as the final step of Example 1 above, from various1H-2-imidazoleamine derivatives and various 2-bromo-1-ethanonederivatives.

Example 22-(3-Benzyl-2-imino-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.40 (18H, s), 5.16 (2H, s), 5.59 (2H, s), 6.96 (1H, s), 7.14 (1H, s),7.26 (2H, d, J=8.0 Hz), 7.32–7.45 (3H, m), 7.74 (2H, s), 7.90 (1H, brs).

Example 32-(3-Benzyl-2-imino-5-phenyl-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.43 (18H, s), 5.35 (2H, s), 5.83 (1H, s), 5.94 (2H, s), 7.20 (1H, s),7.28–7.41 (8H, m), 7.50 (2H, s), 7.83 (2H, s).

Example 42-(3-Benzyl-2-imino-imidazolidin-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrochloride

1H-NMR (DMSO-d6) δ:

1.44 (18H, s), 3.47–3.62 (4H, s), 4.82 (2H, s), 5.48 (2H, s), 5.79 (1H,s), 7.27–7.34 (5H, s), 7.89 (2H, s), 9.09 (2H, brs).

Example 51-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-(3-heptyl-2-imino-2,3-dihydro-imidazol-1-yl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.85 (3H, t, J=6.4 Hz), 1.18–1.34 (8H, m), 1.41 (18H, s), 1.58–1.70 (2H,m), 3.85 (2H, t, J=7.2 Hz), 5.57 (2H, s), 6.91 (1H, d, J=2.4 Hz), 7.11(1H, d, J=2.4 Hz), 7.74 (2H, s), 8.07 (1H, brs).

Example 61-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-(2-imino-3-pyridin-2-ylmethyl-2,3-dihydro-imidazol-1-yl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.41 (18H, s), 5.28 (2H, s), 5.61 (2H, s), 6.96 (1H, d, J=2.0 Hz), 7.12(1H, d, J=2.0 Hz), 7.27 (1H, d, J=7.6 Hz), 7.34–7.40 (1H, m), 7.76 (2H,s), 8.04–8.10 (2H, m), 8.56 (1H, d, J=3.2 Hz).

Example 7 Ethyl4-{3-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-imino-2,3-dihydro-imidazol-1-ylmethyl}-benzoatehydrobromide

1H-NMR (DMSO-d6) δ:

1.30 (3H, t, J=7.2 Hz), 1.41 (18H, s), 4.31 (2H, q, J=7.2 Hz), 5.27 (2H,s), 5.60 (2H, s), 6.98 (1H, d, J=2.0 Hz), 1.17 (1H, d, J=2.0 Hz), 4.37(2H, d, J=8.0 Hz), 7.75 (2H, s), 7.93 (1H, brs), 7.99 (2H, d, J=8.0 Hz).

Example 84-{3-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-imino-2,3-dihydro-imidazol-1-ylmethyl}-benzoicacid trifluoroacetate

1H-NMR (DMSO-d6) δ:

1.41 (18H, s), 5.26 (2H, s), 5.61 (2H, s), 6.98 (1H, d, J=2.0 Hz), 7.18(1H, d, J=2.0 Hz), 7.34 (2H, d, J=8.0 Hz), 7.76 (2H, s), 7.93 (1H, brs),7.98 (2H, d, J=8.0 Hz).

Example 91-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[2-imino-3-(2-methyl-benzyl)-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.42 (18H, s), 2.28 (3H, s), 5.10–5.22 (2H, m), 5.62–5.73 (2H, m),6.75–6.83 (1H, m), 6.93 (1H, brs), 7.01 (1H, brs), 7.18–7.31 (3H, m),7.78 (2H, s), 7.88–8.20 (3H, m).

Example 101-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(6-hydroxy-hexyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.19–1.46 (24H, m), 1.57–1.69 (2H, m), 3.75–3.90 (2H, m), 4.31–4.49 (1H,m), 5.20 (2H, s), 6.86 (1H, d, J=2.4 Hz), 7.02 (1H, d, J=2.4 Hz), 7.34(2H, s), 7.58 (2H, brs).

Example 112-(4-Benzyl-5-imino-4,5-dihydro-[1,2,4]triazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.40 (18H, s), 5.28 (2H, s), 5.85 (2H, s), 7.32–7.50 (5H, m), 7.76 (2H,s), 8.39 (1H, brs), 8.65 (1H, brs), 8.69 (1H, s).

Example 121-Benzyl-3-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-imino-imidazolidin-4-onetrifluoroacetate

1H-NMR (DMSO-d6) δ:

1.41 (18H, s), 4.45 (2H, s), 4.84 (2H, s), 5.35 (2H, s), 7.34–7.47 (5H,m), 7.79 (2H, s), 8.13 (1H, s).

Example 132-(3-Benzyl-2-phenylimino-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.37 (18H, s), 4.84 (2H, s), 5.82 (1H, s), 5.96 (2H, s), 6.68 (1H, s),6.83 (1H, s), 6.89 (1H, t, J=7 Hz), 6.98 (2H, d, J=7 Hz), 7.13–7.30 (4H,m), 7.30–7.35 (3H, m), 7.72 (2H, s).

Example 141-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(2-diethylamino-ethyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.89 (6H, t, J=6.4 Hz), 1.40 (18H, m), 2.37–2.68 (6H, m), 3.89–3.97 (2H,m), 5.57 (2H, s), 6.88 (1H, d, J=3.2 Hz), 7.06 (1H, d, J=3.2 Hz), 7.74(2H, s), 7.82 (2H, brs).

Example 151-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[2-imino-3-(2-piperidin-1-yl-ethyl)-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.27–1.52 (24H, m), 2.30–2.59 (6H, m), 3.92–4.00 (2H, m), 5.56 (2H, s),6.89 (1H, d, J=2.4 Hz), 7.06 (1H, d, J=2.4 Hz), 7.74 (2H, s), 7.91 (2H,brs).

Example 162-[3-(4-Aminomethyl-benzyl)-2-imino-2,3-dihydro-imidazol-1-yl]-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonedihydrochloride

1H-NMR (DMSO-d6) δ:

1.404 (18H, s), 3.95–4.11 (2H, m), 5.23 (2H, s), 5.65 (2H, s), 6.95 (1H,d, J=2.4 Hz), 7.15 (1H, d, J=2.4 Hz), 7.34 (2H, d, J=7.9 Hz), 7.52 (2H,d, J=7.9 Hz), 7.75 (2H, s), 8.08 (2H, s).

Example 17 Methyl4-{1-benzyl-3-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-1,3-dihydro-imidazol-2-ylideneamino}-benzoatehydrobromide

1H-NMR (DMSO-d6) δ:

1.43 (18H, s), 3.84 (3H, s), 5.07 (2H, s), 5.90 (1H, s), 5.99 (2H, s),6.87 (1H, d, J=2 Hz), 6.99 (1H, d, J=2 Hz), 7.04 (2H, d, J=8 Hz),7.24–7.26 (2H, m), 7.37–7.40 (3H, m), 7.77 (2H, s), 7.82 (2H, d, J=8Hz).

Example 184-{1-Benzyl-3-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-1,3-dihydro-imidazol-2-ylideneamino}-benzoicacid hydrobromide

1H-NMR (DMSO-d6) δ:

1.37 (18H, s), 5.14 (2H, s), 5.79 (2H, s), 6.82 (2H, d, J=9 Hz), 7.23(2H, d, J=8 Hz), 7.31–7.38 (3H, m), 7.60, 7.59 (1H, d, J=1 Hz), 7.66(2H, s), 7.76 (1H, d, J=3 Hz), 7.81 (2H, d, J=9 Hz), 8.09 (1H, s), 9.97(1H, s).

Example 192-(3-Benzyl-2-imino-5-methyl-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.45 (18H, s), 1.98 (3H, s), 4.98 (2H, s), 5.60 (2H, s), 6.23 (1H, s),7.20–7.28 (2H, m), 7.33–7.44 (3H, m), 7.88 (2H, s).

Example 202-[3-Benzyl-2-(4-nitro-phenylimino)-2,3-dihydro-imidazol-1-yl]-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrochloride

1H-NMR (DMSO-d6) δ:

1.40 (18H, s), 5.25 (2H, s), 5.70 (2H, s), 6.81 (2H, d, J=9 Hz), 7.22(2H, m), 7.35 (3H, m), 7.59 (1H, d, J=2 Hz), 7.70 (1H, d, J=2 Hz), 7.76(2H, s), 6.89 (2H, d, J=9 Hz).

Example 212-[2-(4-Amino-phenylimino)-3-benzyl-2,3-dihydro-imidazol-1-yl]-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonedihydrochloride

1H-NMR (DMSO-d6) δ:

1.43 (18H, s), 5.15 (2H, s), 5.68 (2H, s), 6.89 (2H, d, J=9 Hz),7.13–7.19 (4H, m), 7.34–7.38 (3H, m), 7.44 (1H, d, J=2 Hz), 7.53 (1H, d,J=2 Hz), 7.78 (2H, s).

Example 22N-{1-Benzyl-3-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-imidazolidin-2-ylidene}-acetamide

1H-NMR (DMSO-d6) δ:

1.46 (18H, s), 2.03 (3H, s), 3.48 (2H, dd, J=11, 7 Hz), 3.67 (2H, dd,J=11, 7 Hz), 4.53 (2H, s), 4.78 (2H, s), 5.80 (1H, s), 7.29–7.38 (5H,m), 7.83 (2H, m).

Example 232-(3-Benzyl-5-ethyl-2-imino-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.16 (3H, t, J=10 Hz), 1.45 (18H, s), 2.33 (2H, q, J=10 Hz), 4.98 (2H,s), 5.52 (2H, s), 6.24 (1H, s), 7.23–7.30 (2H, m), 7.35–7.48 (3H, m),7.86 (2H, s).

Example 242-(2-Benzyl-5-imino-2,5-dihydro-[1,2,4]triazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonetrifluoroacetate

1H-NMR (DMSO-d6) δ:

1.40 (18H, s), 5.44 (2H, s), 5.75 (2H, s), 7.30 (1H, s), 7.35–7.47 (5H,m), 7.75 (2H, s), 8.14 (1H, s), 9.44 (1H, s).

Example 252-(5-Amino-3-benzyl-2-imino-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanoneditrifluoroacetate

1H-NMR (DMSO-d6) δ:

1.41 (18H, s), 4.45 (2H, s), 4.84 (2H, s), 5.34 (2H, s), 7.34–7.48 (5H,m), 7.79 (2H, s), 8.11 (1H, s).

Example 262-(3-Benzyl-2-imino-5-methoxy-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonetrifluoroacetate

1H-NMR (DMSO-d6) δ:

1.40 (18H, s), 3.64 (3H, s), 4.32 (2H, s), 4.75 (2H, s), 7.26 (2H, s),7.20–7.40 (5H, m).

Example 272-(3-Benzyl-2-cyclohexylimino-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrochloride

1H-NMR (DMSO-d6) δ:

0.95–1.03 (2H, m), 1.12–1.23 (2H, m), 1.36–1.45 (2H, m), 1.47 (18H, s),1.59–1.64 (2H, m), 1.70–1.77 (2H, m), 3.07–3.16 (1H, m), 5.30 (2H, s),5.69 (2H, s), 7.14 (1H, d, J=2 Hz), 7.20 (1H, d, J=2 Hz), 7.28–7.47 (5H,m), 7.91 (2H, s)

Example 282-(3-Benzyl-2-benzylimino-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrochloride

1H-NMR (DMSO-d6) δ:

1.49 (18H, s), 4.40 (2H, d, J=6 Hz), 5.12 (2H, s), 5.92 (1H, s), 5.99(2H, s), 6.54 (1H, d, J=3 Hz), 6.61 (1H, d, J=3 Hz), 7.12–7.25 (7H, m),7.37–7.42 (3H, m), 7.87 (2H, m).

Example 291-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-(3-heptyl-2-heptylimino-2,3-dihydro-imidazol-1-yl)-ethanonehydrochloride

1H-NMR (DMSO-d6) δ:

0.79 (3H, t, J=7 Hz), 0.88 (3H, t, J=7 Hz), 1.09–1.43 (16H, m), 1.47(18H, m), 1.60–1.67 (2H, m), 1.79–1.86 (2H, m), 3.25 (2H, q, J=7 Hz),3.96 (2H, t, J=7 Hz), 5.90 (1H, s), 6.17 (2H, s), 6.61 (1H, d, J=3 Hz),6.68 (1H, d, J=3 Hz), 7.97 (2H, s), 9.11 (1H, t, J=7 Hz).

Example 301-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[2-imino-3-(3-methyl-butyl)-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.91 (6H, d, J=6.0 Hz), 1.41 (18H, m), 1.50–1.64 (3H, m), 3.77–3.98 (2H,m), 5.60 (2H, s), 6.93 (1H, d, J=2.4 Hz), 7.13 (1H, d, J=2.4 Hz), 7.75(2H, s), 7.77 (2H, brs), 8.04 (1H, brs).

Example 311-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(2-ethyl-butyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.84 (6H, t, J=7.2 Hz), 1.20–1.32 (4H, m), 1.41 (18H, m), 1.72–1.83 (1H,m), 3.79 (2H, d, J=7.2 Hz), 5.61 (2H, s), 6.94 (1H, brs), 7.10 (1H,brs), 7.67–7.83 (4H, m), 8.03 (1H, brs).

Example 322-[3-(2-Cyclopentyl-ethyl)-2-imino-2,3-dihydro-imidazol-1-yl]-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.41 (18H, s), 1.04–1.76 (11H, m), 3.82–3.88 (2H, m), 5.56 (2H, s), 6.91(1H, d, J=2.0 Hz), 7.13 (1H, d, J=2.0 Hz), 7.74 (2H, s).

Example 332-[3-(2-Cyclohexyl-ethyl)-2-imino-2,3-dihydro-imidazol-1-yl]-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.40 (18H, s), 1.10–1.78 (13H, m), 3.80–3.90 (2H, m), 5.56 (2H, s), 6.91(1H, d, J=2.0 Hz), 7.12 (1H, d, J=2.0 Hz), 7.74 (2H, s).

Example 341-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(4-ethyl-hexyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.81 (6H, d, J=7.2 Hz), 1.13–1.32 (8H, m), 1.41 (18H, m), 1.55–1.67 (1H,m), 3.86 (2H, t, J=6.8 Hz), 5.59 (2H, s), 6.92 (1H, brs), 7.13 (1H,brs), 7.75 (2H, s), 7.77 (2H, brs), 8.05 (1H, brs).

Example 351-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-2-hydroxy-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.87 (6H, t, J=7.2 Hz), 1.15–1.52 (23H, m), 3.65–3.94 (3H, m), 4.98 (1H,d, J=5.6 Hz), 5.59 (2H, s), 6.91 (1H, d, J=2.4 Hz), 7.08 (1H, d, J=2.4Hz), 7.64 (2H, brs), 7.75 (2H, s), 8.06 (1H, brs).

Example 361-{3-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-imino-2,3-dihydro-imidazol-1-yl}-3-ethyl-pentan-2-onehydrobromide

1H-NMR (DMSO-d6) δ:

]0.80 (6H, t, J=7.2 Hz), 1.39 (18H, s), 1.40–1.64 (4H, m), 5.06 (2H,brs), 5.58 (2H, brs), 6.86–6.97 (2H, m), 7.63–7.80 (4H, m), 8.05 (1H,brs)

Example 372-(3-Benzyl-2-imino-4-methyl-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.47 (18H, m), 2.08 (3H, s), 5.33 (2H, s), 5.86 (1H, s), 6.02 (2H, s),6.27 (H, s), 7.17 (2H, d, J=7 Hz), 7.26–7.36 (3H, m), 7.76 (2H, s), 7.95(2H, s).

Example 381-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-3-hydroxy-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.79 (6H, t, J=7.6 Hz), 1.28–1.48 (22H, m), 1.67–1.76 (2H, m), 3.80–3.93(2H, m), 4.28 (1H, s), 5.55 (2H, s), 6.91 (1H, d, J=2.8 Hz), 7.10 (1H,d, J=2.8 Hz), 7.67 (2H, brs), 7.73 (2H, s), 8.05 (1H, brs).

Example 392-(3-Benzyl-5-butyl-2-imino-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.78 (3H, t, J=8.0 Hz), 1.08–1.30 (4H, m), 1.37 (18H, s), 2.08–2.2 (2H,br), 4.93 (2H, s), 5.62 (2H, s), 5.79 (1H, s), 6.05 (1H, s), 7.08–7.35(7H, m), 7.80 (2H, s).

Example 401-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-(2-imino-3-phenethyl-2,3-dihydro-imidazol-1-yl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.41 (18H, s), 2.98 (2H, t, J=8.0 Hz), 4.12 (2H, t, J=8.0 Hz), 5.56 (2H,s), 6.87 (1H, d, J=2.0 Hz), 6.99 (1H, d, J=2.0 Hz), 7.20–7.34 (5H, m),7.75 (2H, s), 7.79 (2H, brs), 8.07 (1H, s).

Example 411-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-(3-imino-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-2-yl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.46 (18H, s), 2.51 (2H, pent, J=7 Hz), 2.80 (2H, t, J=7 Hz), 4.23 (2H,J=7 Hz), 5.83 (1H, s), 5.94 (2H, s), 6.09 (1H, s), 7.93 (2H, s), 8.34(2H, s).

Example 422-[3-(2-Cyclobutylidene-ethyl)-2-imino-2,3-dihydro-imidazol-1-yl]-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.40 (18H, s), 1.94 (2H, pent, J=8 Hz), 2.67 (br.q, J=8 Hz), 4.46 (2H,d, J=8 Hz), 5.21 (1H, tt, J=8, 2 Hz), 5.79 (1H, s), 6.41 (1H, d, J=3Hz), 6.51 (1H, d, J=3 Hz), 7.85 (2H, s), 7.89 (2H, s).

Example 432-[3-(2-Cyclobutyl-ethyl)-2-imino-2,3-dihydro-imidazol-1-yl]-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.46 (18H, s), 1.59–1.70 (2H, m), 1.76–1.91 (4H, m), 2.01–2.09 (2H, m),2.38 (1H, sept, J=8 Hz), 4.45 (2H, t, J=7 Hz), 5.85 (1H, s), 6.02 (2H,s), 6.46 (1H, d, J=3 Hz), 6.50 (1H, d, J=3 Hz), 7.92 (2H, s), 8.18 (2H,s).

Example 441-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[2-imino-3-(3-propyl-hexyl)-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.80–0.94 (6H, m), 1.16–1.34 (9H, m), 1.41 (18H, s), 1.54–1.64 (2H, m),3.88 (2H, t, J=6.0 Hz), 5.59 (2H, s), 6.92 (1H, d, J=2.4 Hz), 7.14 (1H,d, J=2.4 Hz), 7.75 (2H, s), 7.76 (2H, brs), 8.07 (1H, brs).

Example 451-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-pent-2-enyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.90–1.03 (6H, m), 1.41 (18H, s), 2.07 (2H, q, J=7.6 Hz), 2.15 (2H, q,J=7.6 Hz), 4.50 (2H, d, J=6.8 Hz), 5.22 (1H, t, J=6.8 Hz), 5.59 (2H, s),6.92 (1H, d, J=2.4 Hz), 7.00 (1H, d, J=2.4 Hz), 7.75 (2H, s), 7.78 (2H,brs), 8.09 (1H, brs).

Example 461-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-pentyl)-2-imino-4-methyl-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.85 (6H, t, J=7 Hz), 1.32–1.41 (5H, m), 1.47 (18H, s), 1.59–1.66 (2H,m), 2.16 (3H, s), 4.03 (2H, t, J=8 Hz), 5.84 (1H, s), 6.00 (2H, s), 6.21(1H, s), 7.82 (2H, s), 7.95 (2H, s).

Example 471-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-pentyl)-2-imino-4,5-dimethoxy-imidazolidin-1-yl]-ethanonehydrochloride

1H-NMR (DMSO-d6) δ:

Trans

0.83 (3H, t, J=7 Hz), 1.47 (18H, s), 1.23–1.64 (7H, m), 3.33–3.40 (1H,m), 3.34 (3H, s), 3.48 (3H, s), 3.93–3.97 (1H, m), 4.60 (1H, dd, J=19Hz), 4.93 (1H, s), 4.99 (1H, s), 5.82 (1H, s), 6.60 (1H, d, J=19 Hz),7.94 (2H, s):

Cis

0.89 (3H, t, J=7 Hz), 1.47 (18H, s), 1.23–1.64, 7H, m), 3.00–3.05 (1H,m), 3.18–3.25 (1H, m), 3.44 (3H, s), 3.46 (3H, s), 4.58 (1H, d, J=19Hz), 5.03 (1H, d, J=6 Hz), 5.15 (1H, d, J=6 Hz), 5.83 (1H, s), 6.53 (1H,d, J=19 Hz), 7.92 (2H, s).

Example 481-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-3-methoxy-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.76 (6H, t, J=7.2 Hz), 1.41 (18H, s), 1.41–1.51 (4H, m), 1.79 (2H, t,J=7.6 Hz), 3.04 (3H, s), 3.82 (2H, t, J=7.6 Hz), 5.59 (2H, brs), 6.93(1H, d, J=2.4 Hz), 7.16 (1H, d, J=2.4 Hz), 7.72 (2H, brs), 7.75 (2H, s),8.06 (1H, brs).

Example 492-(6-Benzyloxy-3-imino-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-2-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.48 (18H, s), 2.90 (1H, br dd, J=16, 2 Hz), 3.05 (1H, ddd, J=16, 6, 2Hz), 4.38 (1H, dd, J=13, 5 Hz), 4.45 (1H, dd, J=13, 4 Hz), 4.78 (1H, m),5.59 (1H, d, J=20 Hz), 6.03 (1H, dd, J=20 Hz), 6.16 (1H, s9, 7.28–7.37(5H, m), 7.92 (2H, s), 7.98 (1H, brs).

Example 502-[3-(2-Cyclopropyl-ethyl)-2-imino-2,3-dihydro-imidazol-1-yl]-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.00–0.08 (2H, m), 0.32–0.40 (2H, m), 0.56–0.68 (1H, m), 1.38 (18H, s),1.46–1.56 (2H, m), 3.87–3.95 (2H, m), 5.53 (2H, s), 6.88 (1H, s), 7.07(1H, s), 7.71 (2H, s), 8.03 (1H, brs).

Example 517-tert-Butyl-5-{2-[3-(3-ethyl-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-acetyl}-3,3-dimethyl-3H-benzofuran-2-onetrifluoroacetate

1H-NMR (DMSO-d6) δ:

0.82 (6H, t, J=7.2 Hz), 1.13–1.22 (1H, m), 1.28 (4H, q, J=7.2 Hz), 1.38(9H, s), 1.49 (6H, s), 1.54–1.65 (2H, m), 3.88 (2H, t, J=7.6 Hz), 5.61(2H, s), 6.95 (1H, d, J=2.0 Hz), 7.16 (1H, d, J=2.0 Hz), 7.82 (1H, s),7.84 (1H, s), 8.07 (1H, s).

Example 522-(3-Benzyl-5-benzyloxymethyl-2-imino-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrochloride

1H-NMR (DMSO-d6) δ:

1.40 (18H, s), 4.28 (2H, s), 4.42 (2H, s), 5.19 (2H, s), 5.59 (2H, s),7.06–7.17 (5H, m), 7.30 (2H, d, J=7 Hz), 7.35 (1H, t, J=7 Hz), 7.43 (2H,t, J=7 Hz), 7.74 (2H, s), 8.06 (1H, s), 8.09 (2H, s).

Example 532-{3-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-imino-2,3-dihydro-imidazol-1-yl}-N,N-diethyl-acetamidehydrobromide

1H-NMR (DMSO-d6) δ:

0.98–1.04 (3H, m), 1.10–1.20 (3H, m), 1.40 (18H, s), 3.20–3.40 (4H, m),4.88 (2H, s), 5.58 (2H, s), 6.88 (1H, d, J=2.4 Hz), 6.97 (1H, d, J=2.4Hz), 7.65–7.81 (4H, m), 8.01–8.13 (1H, m).

Example 541-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[2-imino-3-(2-propoxy-benzyl)-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.98 (3H, t, J=7.8 Hz), 1.404 (18H, s), 1.68–1.82 (2H, m), 3.97 (2H, t,J=6.4 Hz), 5.07 (2H, s), 5.60 (2H, s), 6.86–7.09 (5H, m), 7.33 (1H, brt,J=7.5 Hz), 7.75 (2H, s), 7.85 (2H, brs).

Example 552-[3-(2-Butyl-benzyl)-2-imino-2,3-dihydro-imidazol-1-yl]-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.91 (3H, t, J=7.0 Hz), 1.30–1.58 (22H, m), 2.59 (2H, brt, J=8.0 Hz),5.18 (2H, s), 5.64 (2H, s), 6.74–6.83 (1H, m), 6.92 (1H, d, J=2.5 Hz),6.98 (1H, d, J=2.5 Hz), 7.15–7.33 (3H, m), 7.768 (2H, s), 7.91 (2H, s),8.07 (1H, s).

Example 561-Benzyl-2-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethylamino]-1H-imidazole-4,5-dicarbonitrilehydrobromide

1H-NMR (DMSO-d6) δ:

1.47 (18H, s), 4.75 (2H, d, J=8 Hz), 5.09 (2H, s), 5.60 (1H, t, J=8 Hz),5.88 (1H, s), 7.34 (2H, d, J=8 Hz), 7.43 (1H, t, J=7 Hz), 7.47 (2H, d,J=7 Hz), 7.81 (2H, s).

Example 572-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethylamino]-1-(3-ethyl-pentyl)-1H-imidazole-4,5-dicarbonitrile

1H-NMR (DMSO-d6) δ:

0.93 (6H, t, J=7 Hz), 1.28–1.35 (1H, m), 1.38–1.46 (4H, m), 1.48 (18H,s), 1.76 (2H, td, J=8, 7 Hz), 3.92 (2H, t, J=8 Hz), 4.82 (2H, d, J=4Hz), 5.60 (1H, t, J=4 Hz), 5.90 (1H, s), 7.85 (2H, s).

Example 582-(3-Benzyl-2-imino-5-propyl-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.85 (3H, t, J=7.2 Hz), 1.36–1.60 (2H, br), 1.40 (18H, s), 2.30 (2H, t,J=7.2 Hz), 5.13 (2H, s), 5.58 (2H, s), 6.92 (1H, s), 7.25–7.42 (5H, m),7.79 (2H, s), 7.86 (2H, s), 8.07 (1H, s).

Example 593-Benzyl-1-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-imino-2,3-dihydro-1H-imidazole-4-carbonitrilehydrobromide

1H-NMR (DMSO-d6) δ:

1.41 (18H, s), 5.32 (2H, s), 5.75 (2H, s), 7.25 (2H, d, J=7 Hz), 7.39(1H, t, J=7 Hz), 7.45 (2H, t, J=7 Hz), 7.84 (2H, s), 8.11 (1H, s), 8.15(1H, s), 8.79 (2H, s).

Example 601-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(3-ethyl-pentyl)-2-imino-2,3-dihydro-1H-imidazole-4-carbonitrilehydrobromide

1H-NMR (DMSO-d6) δ:

0.85 (6H, t, J=7 Hz), 1.20–1.38 (5H, m), 1.40 (18H, s), 1.60 (2H, q, J=6Hz), 4.01 (2H, t, J=6 Hz), 5.70 (2H, s), 8.06 (1H, s), 8.14 (1H, s),8.58 (2H, s).

Example 611-Benzyl-3-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-imino-2,3-dihydro-1H-imidazole-4-carbonitrilehydrobromide

1H-NMR (DMSO-d6) δ:

1.40 (18H, s), 5.24 (2H, s), 5.78 (2H, s), 7.28–7.43 (5H, m), 7.79 (2H,s), 8.18 (1H, s), 8.39 (1H, s), 8.74 (2H, s).

Example 623-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-1-(3-ethyl-pentyl)-2-imino-2,3-dihydro-1H-imidazole-4-carbonitrilehydrobromide

1H-NMR (DMSO-d6) δ:

0.82 (6H, t, J=7 Hz), 1.15–1.24 (1H, m), 1.16–1.24 (4H, m), 1.41 (18H,s), 1.62 (2H, q, J=7 Hz), 3.94 (2H, t, J=7 Hz), 5.77 (2H, s), 7.79 (2H,s), 8.18 (1H, s), 8.42 (1H, s), 8.61 (2H, s).

Example 632-[5-Benzyl-3-(3-ethyl-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.80 (6H, t, J=7.2 Hz), 1.10–1.60 (7H, m), 3.75 (2H, s), 3.77–3.86 (2H,m), 5.45 (2H, s), 6.73 (1H, s), 7.10–7.24 (5H, m), 7.64 (2H, s), 7.70(2H, brs), 8.03 (1H, s).

Example 641-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanoneoxime hydrobromide

1H-NMR (DMSO-d6) δ:

0.78 (6H, t, J=7 Hz), 1.15–1.24 (1H, m), 1.16–1.24 (4H, m), 1.41 (18H,s), 1.65 (2H, q, J=7 Hz), 4.11 (2H, t, J=7 Hz), 5.21 (2H, s), 5.45 (1H,s), 6.44 (1H, s), 6.48 (1H, s), 7.41 (2H, s), 7.86 (2H, s).

Example 652-(3-Benzyl-2-imino-4-propyl-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.82 (3H, t, J=7.2 Hz), 1.36–1.50 (2H, br), 1.41 (18H, s), 2.32 (2H, t,J=7.2 Hz), 5.22 (2H, s), 5.62 (2H, s), 6.77 (1H, s), 7.13 (2H, d, J=7.6Hz), 7.30–7.43 (3H, m), 7.76 (2H, s), 7.88 (2H, s), 8.06 (1H, s).

Example 66 Ethyl3-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-2-oxo-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-acrylatehydrochloride

1H-NMR (DMSO-d6) δ:

0.71–0.92 (6H, m), 1.10–1.72 (25H, m), 2.43–2.60 (1H, m), 4.09–4.32 (2H,m), 5.10 (1H, d, J=18.0 Hz), 5.18 (1H, d, J=18.0 Hz), 7.08 (1H, d, J=2,8 Hz), 7.15 (1H, d, J=2, 8 Hz), 7.93–8.01 (1H, m), 8.06 (2H, s).

Example 672-[3-(2-Bicyclo[2.2.1]hept-7-yl-ethyl)-2-imino-2,3-dihydro-imidazol-1-yl]-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.10–1.18 (4H, m), 1.32–1.64 (7H, m), 1.41 (18H, s), 1.91–1.96 (2H, m),3.86 (2H, t, J=7.2 Hz), 5.57 (2H, s), 6.90 (1H, d, J=2.0 Hz), 7.13 (1H,d, J=2.0 Hz), 7.74 (2H, s).

Example 68N-(2-Bromo-4-{2-[3-(3-ethyl-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-acetyl}-phenyl)-2,2-dimethyl-propionamidehydrobromide

1H-NMR (DMSO-d6) δ:

0.82 (6H, t, J=7.5 Hz), 1.10–1.66 (16H, m), 3.87 (2H, t, J=7.6 Hz),5.578 (2H, s), 6.95 (1H, brs), 7.16 (1H, brs), 7.70–8.03 (4H, m), 8.246(1H, s), 9.09 (1H, s).

Example 691-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[2-imino-3-(2-piperidin-1-yl-ethyl)-4-propyl-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.96 (3H, t, J=7.2 Hz), 1.28–1.87 (8H, m), 1.38 (18H, s), 2.50 (2H, t,J=7.2 Hz), 2.87–3.06 (2H, br), 3.20–3.35 (2H, br), 3.44–3.70 (2H, br),4.20–4.30 (2H, br), 5.55 (2H, s), 6.70 (1H, s), 7.72 (2H, s), 7.96 (2H,s), 8.08 (1H, s).

Example 701-{3-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-imino-2,3-dihydro-imidazol-1-yl}-3-ethyl-1-fluoro-pentan-2-onehydrochloride

1H-NMR (DMSO-d6) δ:

0.80 (3H, t, J=7.2 Hz), 0.85 (3H, t, J=7.2 Hz), 1.40 (18H, s), 1.45–1.73(4H, m), 2.77–2.84 (1H, m), 5.62 (2H, s), 6.96–7.15 (3H, m), 7.75 (2H,s), 8.09 (1H, brs), 8.51–8.63 (2H, m).

Example 71 Ethyl1-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(3-ethyl-pentyl)-2-imino-2,3-dihydro-1H-imidazole-4-carboxylatehydrobromide

1H-NMR (DMSO-d6) δ:

0.83 (6H, t, J=7 Hz), 1.21–1.35 (5H, m), 1.26 (3H, t, J=7 Hz), 1.42(18H, s), 1.54 (2H, q, J=8 Hz), 4.21 (2H, t, J=8 Hz), 4.28 (2H, q, J=7Hz), 5.64 (2H, s), 7.74 (2H, s), 7.86 (1H, s), 8.12 (1H, s), 8.30 (2H,s).

Example 721-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-pentyl)-4,5-bis-hydroxymethyl-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.84 (6H, t, J=7 Hz), 1.25–1.38 (5H, m), 1.42 (18H, s), 1.55–1.62 (2H,m), 3.93 (2H, t, J=8 Hz), 4.31 (2H, t, J=5 Hz), 4.42 (2H, d, J=5 Hz);5.17 (1H, t, J=5 Hz), 5.37 (1H, t, J=5 Hz), 5.53 (2H, s)l, 7.76 (2H, s),7.77 (2H, s), 8.06 (1H, s).

Example 731-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-pentyl)-4-hydroxymethyl-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.84 (6H, t, J=7 Hz), 1.25–1.38 (5H, m), 1.41 (18H, s), 1.55–1.61 (2H,m), 3.92 (2H, t, J=8 Hz), 4.39 (2H, d, J=6 Hz), 5.45 (1H, t, J=6 Hz),5.57 (2H, s), 6.85 (1H, s), 7.74 (4H, s), 8.06 (1H, s).

Example 741-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-pentyl)-5-hydroxymethyl-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.83 (6H, t, J=7 Hz), 1.16–1.24 (1H, m), 1.25–1.35 (4H, m), 1.41 (18H,s), 1.58 (2H, q, J=7 Hz), 3.85 (2H, t, J=7 Hz), 4.23 (2H, d, J=5 Hz),5.30 (1H, t, J=5 Hz), 5.53 (2H, s), 7.76 (4H, s), 8.07 (1H, s).

Example 751-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-pentyl)-2-imino-4-(morpholine-4-carbonyl)-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.82 (6H, t, J=7 Hz), 1.28–1.36 (5H, m), 1.46 (18H, s), 1.57–1.65 (2H,m), 3.71 (8H, s), 4.25 (2H, t, J=9 Hz), 5.87 (1H, s), 6.14 (2H, s), 6.67(1H, s), 7.94 (2H, s), 8.23 (2H, s).

Example 76 Ethyl4-{3-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-imino-5-propyl-2,3-dihydro-imidazol-1-ylmethyl}-benzoatehydrobromide

1H-NMR (DMSO-d6) δ:

0.82 (3H, t, J=7.2 Hz), 1.29 (3H, t, J=7.0 Hz), 1.32–1.48 (2H, br), 1.41(18H, s), 2.30 (2H, t, J=7.2 Hz), 4.30 (2H, q, J=7.0 Hz), 5.30 (2H, s),5.60 (2H, s), 6.78 (1H, s), 7.25 (2H, d, J=8.4 Hz), 7.76 (2H, s), 7.89(2H, br), 7.99 (2H, d, J=8.4 Hz), 8.07 (1H, s).

Example 774-{3-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-imino-5-propyl-2,3-dihydro-imidazol-1-ylmethyl}-benzoicacid hydrobromide

1H-NMR (DMSO-d6) δ:

0.82 (3H, t, J=7.2 Hz), 1.36–1.45 (2H, br), 1.40 (18H, s), 2.31 (2H, t,J=7.2 Hz), 5.34 (2H, s), 5.68 (2H, s), 6.77 (1H, s), 7.23 (2H, d, J=8.4Hz), 7.76 (2H, s), 7.95 (2H, d, J=8.4 Hz), 8.10 (2H, s).

Example 781-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(2-hydroxy-ethyl)-2-imino-4-propyl-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.94 (3H, t, J=6.8 Hz), 1.40 (18H, s), 1.45–1.58 (2H, m), 2.43–2.52 (2H,m), 3.57–3.62 (2H, br), 3.87–3.93 (2H, br), 5.51 (2H, s), 6.64 (1H, s),7.60 (1H, s), 7.74 (2H, s), 8.30 (1H, s).

Example 791-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-(2-imino-4-propyl-2,3-dihydro-imidazol-1-yl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

5.94 (3H, t, J=7 Hz), 1.47 (18H, s), 1.63 (2H, hex, J=7 Hz), 2.44 (2H,t, J=7 Hz), 5.40 (2H, s), 6.17 (1H<s), 6.28 (2H, brs), 7.87 (2H, s).

Example 801-(7-tert-Butyl-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-2-[3-(3-ethyl-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.86 (6H, t, J=7.2 Hz), 1.36–1.40 (5H, m), 1.39 (15H, s), 1.61–1.64 (2H,m), 3.71 (2H, t, J=10.0 Hz), 4.32 (2H, s), 5.43 (2H, s), 6.32–6.37 (2H,m), 7.80 (1H, s), 7.84 (1H, s).

Example 811-(3-tert-Butyl-5-dimethylamino-4-hydroxy-phenyl)-2-[3-(3-ethyl-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.77–0.87 (6H, m), 1.10–1.67 (16H, m), 2.60 (6H, s), 3.87 (2H, brt,J=7.5 Hz), 5.54 (2H, s), 6.93 (1H, s), 7.14 (1H, s), 7.61 (1H, s), 7.68(1H, s), 7.74 (2H, brs).

Example 821-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-{3-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-imino-4-propyl-2,3-dihydro-imidazol-1-yl}-ethanonehydrochloride

1H-NMR (DMSO-d6) δ:

0.94 (3H, t, J=7 Hz), 1.46 (18H, s), 1.47 (18H, s), 1.58 (2H, m), 2.23(2H, t, J=7 Hz), 5.75 (2H, s), 5.83 (2H, s), 6.25 (1H, s), 7.90 (2H, s),7.94 (2H, s).

Example 831-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-hydroxy-propyl)-2-imino-4-propyl-2,3-dihydro-imidazol-1-yl]-ethanone hydrbromide

1H-NMR (DMSO-d6) δ:

0.95 (3H, t, J=7.6 Hz), 1.41 (18H, s), 1.51–1.57 (2H, m), 1.70–1.80 (2H,m), 2.41–2.54 (2H, br), 3.40–3.46 (2H, br), 3.89 (2H, t, J=7.2 Hz), 5.52(2H, s), 6.66 (1H, s), 7.64 (2H, s), 7.74 (2H, s), 8.05 (1H, s).

Example 84 Ethyl1-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(3-ethyl-pentyl)-2-methylimino-2,3-dihydro-1H-imidazole-4-carboxylatehydrobromide

1H-NMR (DMSO-d6) δ:

0.88 (3H, t, J=7 Hz), 1.27–1.40 (5H, m), 1.49 (18H, s), 1.71–1.77 (2H,m), 3.17 (3H, d, J=5 Hz), 4.33 (2H, t, J=7 Hz), 4.44 (2H, t, J=6 Hz),5.93 (1H, s), 6.26 (2H, s), 7.27 (1H, s), 7.96 (2H, s), 9.14 (1H, q, J=5Hz),

Example 851-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[6-(2-ethyl-butyl)-3-imino-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-2-yl]-ethanonehydrochloride

1H-NMR (DMSO-d6) δ:

0.86 (6H, t, J=7 Hz), 1.23–1.54 (7H, m), 1.48 (18H, s), 2.45 (1H, dd,J=14, 8 Hz), 2.95 (1H, dd, J=14, 8 Hz), 3.02 (1H, quint, J=8 Hz), 3.65(1H, dd, J=11, 8 Hz), 4.43 (1H, dd, J=11, Hz), 5.83 (1H, d, J=18 Hz),5.92 (1H, d, J=18 Hz), 6.13 (1H, s), 7.65 (2H, s), 7.93 (2H, s).

Example 861-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-pentyl)-4-hydroxymethyl-2-methylimino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.88 (6H, t, J=7 Hz), 1.21–1.43 (5H, m), 1.47 (18H, s), 1.72–1.81 (2H,m), 2.60 (1H, t, J=4 Hz), 3.10 (3H, d, J=5 Hz), 4.13 (2H, t, J=8 Hz),4.57 (2H, d, J=4 Hz), 5.91 (1H, s), 6.07 (2H, s), 6.55 (1H, s), 7.94(2H, s), 8.83 (1H, q, J=5 Hz).

Example 871-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-pentyl)-2-imino-4-phenyl-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.57 (6H, t, J=7.2 Hz), 0.93–1.09 (m, 3H), 1.20–1.36 (4H, m), 1.41 (18H,s), 3.93–3.96 (2H, m), 5.62 (2H, s), 7.06 (1H, s), 7.50 (5H, br), 7.74(2H, s), 7.96 (2H, brs).

Example 881-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-pentyl)-4-methyl-2-methylimino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.84 (6H, t, J=7 Hz), 1.16–1.23 (1H, m), 1.25–1.36 (4H, m), 1.43 (18H,s), 1.60–1.67 (2H, m), 2.15 (3H, d, J=1 Hz), 2.96 (3H, d, J=5 Hz), 3.90(2H, t, J=8 Hz), 5.83 (1H, s), 5.96 (2H, s), 6.25 (1H, q, J=1 Hz), 7.87(2H, s), 8.13 (1H, q, 5 Hz).

Example 891-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-2-fluoro-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.89 (6H, t, J=7.2 Hz), 1.31–1.44 (4H, m), 1.39 (18H, s), 1.46–1.58 (1H,m), 4.17–4.27 (2H, m), 4.64–4.85 (1H, m), 5.59 (2H, s), 6.95 (1H, s),7.17 (1H, s), 7.75 (2H, s), 7.83 (2H, brs), 8.05 (1H, br).

Example 901-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-2,2-difluoro-3-methoxy-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.87 (6H, t, J=7.0 Hz), 1.39 (18H, s), 1.67–1.76 (4H, m), 3.25 (s, 3H),4.52–4.63 (2H, m), 5.59 (2H, s), 6.96 (1H, s), 7.04 (1H, s), 7.64 (2H,s), 7.85 (1H, s).

Example 912-(3-Benzyl-4-hydroxymethyl-2-methylimino-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.40 (18H, s), 2.78 (3H.d.J=6.0 Hz), 4.28 (2H.d.J=6.0 Hz), 5.40 (2H. s),5.54 (1H.t.J=6.0 Hz), 5.77 (2H. s), 7.03 (1H. s), 7.16 (2H.d.J=8.0 Hz),7.35 (1H.d.J=8.0 Hz), 7.42 (2H.t.J=8.0 z), 7.51 (1H. m), 7.76 (2H. s).

Example 922-(3-Benzyl-2-imino-4-trifluoromethyl-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonetrifluoroacetate

1H-NMR (DMSO-d6) δ:

1.39 (18H, s), 5.32 (2H, s), 5.66 (s, 2H), 7.14 (2H, d, J=7.2 Hz),7.31–7.37 (1H, m), 7.39–7.46 (2H, m), 7.73 (s, 2H) 7.94 (s, 1H).

Example 932-[3-Benzyl-2-(2-fluoro-benzylimino)-4-methyl-2,3-dihydro-imidazol-1-yl]-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonetrifluoroacetate

1H-NMR (DMSO-d6) δ:

1.46 (18H. s), 2.0 (3H. s), 4.30 (2H. s), 5.18 (2H. s), 5.71 (2H. s),6.51 (1H. s), 6.80 (1H. m), 6.97 (1H.d.J=8.0 Hz), 7.07 (2H. m), 7.24(2H. m), 7.40 (3H. m), 7.78 (2H. s).

Example 943-Benzyl-1-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-imino-2,3-dihydro-1H-imidazole-4-carboxylicacid dimethylamide hydrobromide

1H-NMR (DMSO-d6) δ:

1.40 (18H. s), 2.85 (6H. s), 5.32 (2H. s), 5.65 (2H. s), 7.13(2H.d.J=8.0 Hz), 7.32 (1H. m), 7.38 (2H. m), 7.43 (1H. s), 7.75 (2H. s),8.27 (1H.brs).

Example 953-Benzyl-1-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-methylimino-2,3-dihydro-1H-imidazole-4-carboxylicacid dimethylamide hydrobromide

1H-NMR (DMSO-d6) δ:

1.40 (18H. s), 2.85 (6H. s), 2.90 (3H. s), 5.40 (2H. s), 5.77 (2H. s),7.12 (2H.d.J=8.0 Hz), 7.33 (1H. m), 7.39 (2H. m), 7.48 (1H. s), 7.75(2H. s).

Example 96 Ethyl3-benzyl-1-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-propylimino-2,3-dihydro-1H-imidazole-4-carboxylatehydrobromide

1H-NMR (DMSO-d6) δ:

0.66 (3H, t, J=6.0 Hz), 1.27 (3H, t, J=6.0 Hz), 1.50 (18H, s), 1.58 (2H,m), 3.20 (2H, q, H=6.0 Hz), 4.26 (2H, q, J=6.0 Hz), 5.60 (2H, s), 6.40(2H, s), 7.16 (2H, d, J=8.0 Hz), 7.34 (4H, m), 7.98 (2H, m).

Example 972-(3-Benzyl-4-methyl-2-propylimino-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.65 (3H.t.J=6.0 Hz), 1.42 (2H, m), 1.48 (18H. s), 2.10 (3H. s), 3.02(2H.q.J=6.0 Hz), 3.85 (1H. s), 5.26 (2H. s), 5.93 (2H. s), 7.17(2H.d.J=8.0 Hz), 7.40 (3H. m), 7.83 (1H. s), 7.96 (2H. s).

Example 983-Benzyl-1-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-imino-2,3-dihydro-1H-imidazole-4-carboxylicacid ethyl amide

1H-NMR (DMSO-d6) δ:

1.00 (3H.t, J=6.0 Hz), 1.40 (18H. s), 3.13 (2H.q.J=6.0 Hz), 5.54 (2H.s), 5.70 (2H. s), 7.14 (2H.d.J=8.0 Hz), 7.30 (1H. m), 7.36 (2H. m), 7.52(1H. s), 7.74 (2H. s).

Example 992-[3-Benzyl-2-imino-4-(pyrrolidine-1-carbonyl)-2,3-dihydro-imidazol-1-yl]-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

1.45 (18H. s), 1.60 (4H. m), 3.49 (4H. m), 5.50 (2H. s), 6.20 (2H. s),7.30 (4H. m), 7.92 (1H. m), 7.96 (2H. s).

Example 100 Ethyl3-benzyl-1-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-2-isobutylimino-2,3-dihydro-1H-imidazole-4-carboxylatehydrobromide

1H-NMR (DMSO-d6) δ:

0.63 (6H.d.J=6.0 Hz), 1.19 (3H.t.J=6.0 Hz), 1.43 (18H. s), 1.80 (1H. m),3.00 (2H.d.J=6.0 Hz), 4.19 (wH.q.J=6.0 Hz), 5.54 (2H. s), 6.33 (2H. s),7.1882H.d.J=8.0 Hz), 7.24–7.35 (4H. m), 7.91 (2H. s).

Example 1011-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-pentyl)-2-imino-4-methyl-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

1H-NMR (DMSO-d6) δ:

0.84 (6H, t, J=7.2 Hz), 1.26–1.35 (5H, m), 1.52–1.59 (2H, m), 3.92–3.98(2H, m), 5.66 (2H, s), 7.74 (2H, s), 7.84 (1H, s).

Example 102 Methyl[1-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(3-ethyl-2-oxo-pentyl)-1,3-dihydro-imidazol-2-ylidene]-carbamate

1H-NMR (DMSO-d6) δ:

0.89 (6H, t, J=7.5 Hz), 1.45 (18H, s), 1.45–1.76 (4H, m), 2.40–2.48 (1H,m), 3.57 (3H, s), 4.87 (2H, s), 5.33 (2H, s), 5.82 (1H, s), 6.58 (1H, d,J=3.1 Hz), 6.66 (1H, d, J=3.1 Hz), 7.83 (2H, s).

Example 103 Methyl[1-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(3-ethyl-3-hydroxy-pentyl)-1,3-dihydro-imidazol-2-ylidene]-carbamate

1H-NMR (DMSO-d6) δ:

0.88 (6H, t, J=7.5 Hz), 1.40–1.70 (22H, m), 1.90–1.96 (2H, m), 3.60 (3H,s), 3.93–4.00 (2H, m), 5.30 (2H, s), 5.82 (1H, s), 6.64 (1H, d, J=2.7Hz), 6.66 (1H, d, J=2.7 Hz), 7.81 (2H, s).

Example 104 Methyl[1-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(3-ethyl-pent-2-enyl)-1,3-dihydro-imidazol-2-ylidene]-carbamate

1H-NMR (DMSO-d6) δ:

1.00 (3H, t, J=7.5 Hz), 1.02 (3H, t, J=7.5 Hz), 1.45 (18H, s), 2.03–2.19(4H, m), 3.62 (3H, s), 4.47 (2H, d, J=7.3 Hz), 5.26 (1H, t, J=7.3 Hz),5.31 (2H, s), 5.82 (1H, brs), 6.62 (2H, brs), 7.82 (2H, s).

Example 1051-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(2-ethyl-butyl)-1,3-dihydro-imidazol-2-ylidenecarbamoyloxymethylacetate

1H-NMR (DMSO-d6) δ:

0.88 (6H, t, J=7.5 Hz), 1.19–1.38 (4H, m), 1.45 (18H, s), 1.68–1.81 (1H,m), 1.95 (3H, s), 3.83 (2H, d, J=7.1 Hz), 5.34 (2H, s), 5.73 (2H, s),5.83 (1H, s), 6.64 (1H, brs), 6.67 (1H, brs), 7.82 (2H, s).

Example 1061-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(3-ethyl-2-oxo-pentyl)-1,3-dihydro-imidazol-2-ylidenecarbamoyloxymethylacetate

1H-NMR (DMSO-d6) δ:

0.91 (6H, t, J=7.8 Hz), 1.46 (18H, s), 1.47–1.77 (4H, m), 1.97 (3H, s),2.41–2.50 (1H, m). 4.86 (2H, s), 5.38 (2H, s), 5.70 (2H, s), 5.82 (1H,s), 6.63 (1H, brs), 6.68 (1H, d, J=2.4 Hz), 7.83 (2H, s).

Example 1071-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(3-ethyl-3-hydroxy-pentyl)-1,3-dihydro-imidazol-2-ylidenecarbamoyloxymethylacetate

1H-NMR (DMSO-d6) δ:

0.89 (6H, t, J=7.5 Hz), 1.42–1.56 (22H, m), 1.87–1.95 (2H, m), 1.98 (3H,s), 3.95–4.04 (2H, m), 5.34 (2H, s), 5.73 (2H, s), 5.84 (1H, s), 6.66(1H, brs), 6.70 (1H, brs), 7.83 (2H, s).

Example 1081-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(3-ethyl-pent-2-enyl)-1,3-dihydro-imidazol-2-ylidenecarbamoyloxymethylacetate

1H-NMR (DMSO-d6) δ:

1.01 (3H, t, J=7.5 Hz), 1.03 (3H, t, J=7.5 Hz), 1.44 (18H, s), 1.98 (3H,s), 2.06–2.20 (4H, m), 4.48 (2H, d, J=7.7 Hz), 5.26 (1H, t, J=7.7 Hz),5.34 (2H, s), 5.74 (2H, s), 5.83 (1H, s), 6.64 (1H, brs), 6.66 (1H,brs), 7.83 (2H, s).

Example 1091-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(3-ethyl-2-fluoro-pentyl)-1,3-dihydro-imidazol-2-ylidenecarbamoyloxymethylAcetate

1H-NMR (DMSO-d6) δ:

0.93 (6H, t, J=7.4 Hz), 1.27–1.65 (23H, m), 1.97 (3H, s), 3.88 (1H, ddd,J=9.1, 15.4, 18.8 Hz), 4.37 (1H, dd, J=14.4, 34.1 Hz), 4.68–4.89 (1H,m), 5.32 (1H, d, J=17.3 Hz), 5.41 (1H, d, J=17.3 Hz), 5.71 (1H, d, J=4.8Hz), 5.73 (1H, d, J=4.8 Hz), 5.84 (1H, s), 6.67 (1H, brs), 6.87 (1H,brs), 7.82 (2H, s).

Example 1101-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(3-ethyl-2-oxo-pentyl)-1,3-dihydro-imidazol-2-ylidenecarbamoyloxymethyl2,2-dimethyl-propionate

1H-NMR (DMSO-d6) δ:

0.90 (6H, t, J=7.7 Hz), 1.11 (9H, s), 1.45 (18H, s), 1.47–1.77 (4H, m),2.41–2.50 (1H, m), 4.84 (2H, s), 5.39 (2H, s), 5.70 (2H, s), 5.83 (1H,s), 6.65 (1H, d, J=2.4 Hz), 6.67 (1H, d, J=2.4 Hz), 7.82 (2H, s).

Example 1111-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(3-ethyl-3-hydroxy-pentyl)-1,3-dihydro-imidazol-2-ylidenecarbamoyloxymethyl2,2-dimethyl-propionate

1H-NMR (DMSO-d6) δ:

0.89 (6H, t, J=7.9 Hz), 1.12 (9H, s), 1.40–1.68 (22H, m), 1.87–1.96 (2H,m), 3.99 (2H, dd, J=7.9, 7.1 Hz), 5.35 (2H, s), 5.74 (2H, s), 5.83 (1H,s), 6.65 (1H, brs), 6.70 (1Hbrs), 7.81 (2H, s).

Example 1121-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(3-ethyl-3-methoxy-pentyl)-1,3-dihydro-imidazol-2-ylidenecarbamoyloxymethyl2,2-dimethyl-propionate

1H-NMR (DMSO-d6) δ:

0.92 (6H, t, J=7.3 Hz), 1.06 (9H, s), 1.15–1.71 (22H, m), 1.83–1.93 (2H,m), 3.15 (3H, s), 3.86–3.95 (2H, m), 5.35 (2H, s), 5.74 (2H, s), 5.83(1H, s), 6.64 (1H, brs), 6.70 (1H, brs), 6.67 (1H, d, J=2.4 Hz), 7.81(2H, s).

Example 113 Methyl[1-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(2-ethyl-butyl)-1,3-dihydro-imidazol-2-ylidene]-carbamate

1H-NMR (DMSO-d6) δ:

0.89 (6H, t, J=7.4 Hz), 1.26–1.37 (4H, m), 1.46 (18H, s), 1.68–1.78 (1H,m), 3.60 (3H, s), 3.82 (2H, d, J=7.0 Hz), 5.32 (2H, s), 5.81 (1H, s),6.60 (1H, d, J=2.6 Hz), 6.64 (1H, d, J=2.6 Hz), 7.82 (2H, s).

Example 1142-(3-Benzenesulfonyl-2-imino-2,3-dihydro-imidazol-1-yl)-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrochloride

1H-NMR (DMSO-d6) δ:

1.45 (18H, s), 5.89 (1H, s), 6.11 (2H, s), 6.55 (1H, d, J=3 Hz), 7.01(1H, d, J=3 Hz), 7.69 (2H, d, J=7 Hz), 7.84 (1H, t, J=8 Hz), 7.92 (2H,s), 8.00 (2H, d, J=8 Hz).

Example 1153-Benzyl-1-[2-(3,5-di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3H-imidazol-1-ium

1H-NMR (DMSO-d6) δ:

1.48 (18H, s), 5.48 (2H, s), 5.95 (1H, s), 6.21 (2H, s), 7.09 (1H, t,J=2 Hz), 7.29 (1H, J=2 Hz), 7.41–7.46 (6H, m), 7.88 (2H, s

Example 1161-[2-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-oxo-ethyl]-3-(4-sulfamoyl-benzyl)-3H-imidazol-1-ium

1H-NMR (DMSO-d6) δ:

1.40 (18H, s), 5.61 (2H, s), 5.99 (2H, s), 7.43 (3H, s), 7.57 (2H, d,J=8 Hz), 7.67 (1H, s), 7.87 (2H, d, J=8 Hz), 8.15 (2H, s), 9.18 (2H, s).

Example 1171-(3,5-Di-tert-butyl-4-hydroxy-phenyl)-2-[3-(3-ethyl-pentyl)-2-methylimino-2H-pyridin-1-yl]-ethanonehydrobromide

1H-NMR(DMSO-d6) δ:

0.79 (6H, t, J=7 Hz), 1.15–1.23 (1H, m), 1.23–1.32 (6H, m), 1.43 (18H,s), 2.58 (2H, m), 2.99 (3H, s), 4.66 (2H, s), 6.83 (1H, dd, J=8, 5 Hz),7.42 (1H, dd, J=8, 2 Hz), 7.83 (2H, s), 8.06 (1H, dd, J=5, 2 Hz).

Example 118(2-tert-Butyl-4-{2-[3-(3-ethyl-pent-2-enyl)-2-imino-2,3-dihydro-imidazol-1-yl]-acetyl}-6-pyrrolidin-1-yl-phenoxy)-aceticacid hydrobromide

MS:m/e (ESI)497.5 (MH+)

Example 1195-(2-tert-Butyl-4-{2-[3-(3-ethyl-3-methoxy-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-acetyl}-6-pyrrolidin-1-yl-phenoxy)-pentanoicacid hydrobromide

MS:m/e(ESI)571.5 (MH+)

Example 1205-(2-tert-Butyl-4-{2-[3-(3-ethyl-pent-2-enyl)-2-imino-2,3-dihydro-imidazol-1-yl]-acetyl}-6-pyrrolidin-1-yl-phenoxy)-pentanoicacid hydrobromide

MS:m/e(ESI)539.5 (MH+)

Example 1211-(8-tert-Butyl-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-2-[3-(3-ethyl-3-methoxy-pentyl)-2-imino-2,3-dihydro-imidazol-1-yl]-ethanonehydrobromide

MS:m/e(ESI)457.5 (MH+)

TEST EXAMPLES

The biochemical activities of compounds of the invention and saltsthereof and their actions and effects as medicines (thrombin receptorbinding capacity, platelet aggregation inhibitory action and smoothmuscle cell proliferation inhibitory action) were evaluated by thefollowing methods.

Test Example 1

[Receptor Binding Assay]

Blood was sampled from a healthy adult who had taken no drugs for oneweek, and 3.8% citric acid (a ratio of 1:9 with respect to the blood)was added as an anticoagulant. The mixture was then centrifuged at 100 gfor 10 minutes at room temperature to yield platelet rich plasma (PRP).The platelet precipitate obtained by centrifuging the PRP washomogenized with a Dounce homogenizer, and then centrifuged at 40,000 gfor 60 minutes to yield platelet membrane. The platelet membrane wassuspended in a solution prepared by adding DMSO (dimethyl sulfoxide) at1% concentration to Buffer 1: a 50 mM Tris-HCl buffer containing 10 mMMgCl₂ and 1 mM EGTA (ethylene glycol tetraacetic acid), and thesuspension was stored at −80° C. Bovine albumin and DMSO were added toBuffer 1 at 0.1% and 20%, respectively, to make a preparation solutionfor the test compound. The test compounds (20 μl) diluted at variousconcentrations with the preparation solution were added to a 96-wellmultiscreen plate. Next, 80 μl of 25 nM[³H]Ala-(4-fluoro)Phe-Arg-(cyclohexyl)Ala-(homo)Arg-Tyr-NH₂ (highaffinity TRAP) diluted with Buffer 1 was added and thoroughly mixedtherewith. After then adding 100 μl of the previously prepared plateletmembrane suspension (0.4 mg/ml) and mixing, incubation was performed at37° C. for 1 hour. The reaction mixture was suction filtered and thenrinsed 3 times with 200 μl of Buffer 1. Next, 30 μl of liquidscintillator was added for measurement of the radioactivity of the plateusing a Top Counter (Packard), the value of the radioactivity in thepresence of the test compound minus non-specific binding portion wasdivided by the specific binding value (the value of the binding in theabsence of the compound minus the non-specific binding portion) todetermine the binding ratio, from which the IC₅₀ value was calculated.The non-specific binding was the value obtained with addition of 10 μMof high affinity TRAP. The results are shown in Table 1.

Test Example 2

[Inhibitory Effects on Platelet Aggregation Using Platelet Rich Plasma]

Blood was sampled from a healthy adult who had taken no drugs for oneweek, and 3.8% citric acid (a ratio of 1:9 with respect to the blood)was added as an anticoagulant. The mixture was then centrifuged at 100 gfor 10 minutes at room temperature to yield platelet rich plasma (PRP).The PRP-removed blood was further centrifuged at 1000 g for 10 minutesto yield platelet poor plasma (PPP). The number of platelet was countedusing a multi-parameter automatic hemocyte counter (K4500, Sysmex), andthe PRP was diluted to approximately 300,000/μl with the PPP. Theplatelet aggregation activity was determined in the following mannerusing an Aggregometer (MC Medical). GPRP-NH₂ (final concentration 1 mM,25 μl) was added as a fibrin polymerization inhibitor to the PRP (175μl), after which Ca-free Tyrode solution (control) or the test compoundsuspension (25 μl) at different concentrations was added, incubation wasperformed at 37° C. for 3 minutes and then 25 μl of thrombin at theminimum concentration required to produce maximum aggregation (finalconcentration: optimum concentration among 0.5–1.5 units/ml) was added,for initiation of platelet aggregation. PRP and Ca-free Tyrode solution(control) or the preparation solution at various concentrations werepre-incubated at 37° C. for 60 minutes, prior to the plateletaggregation reaction in some experiments. After addition of thrombin,the aggregation reaction was examined for 6 minutes and the areas underthe aggregation curves were compared to determine the inhibition ratio,from which the IC₅₀ value was calculated. The results are shown in Table1.

Test Example 3

[Rat Smooth Muscle Cell Proliferation Assay]

Vascular smooth muscle cells (rSMC) were isolated from male SD rat aortaby the explant method. DMEM medium (Sigma) containing 10% fetal bovineserum (GibcoBRL), streptomycin and penicillin was used as theproliferation medium, and subculture was carried out at 37° C. in thepresence of 5% CO₂. Culture was initiated after adding 100 μl of rSMCsuspension in proliferation medium at a concentration of 1×10⁴ cells/ml,to a 96-well plate. After 3 days, cells were rinsed twice with 100 μl ofDMEM medium, the medium was exchanged with 100 μl of DMEM mediumcontaining 0.1% albumin (starvation medium), and serum starvation wasinitiated. The medium was exchanged two days after the serum starvation,80 μl of starvation medium and 10 μl of the test compound diluted todifferent concentrations with the starvation medium were added, and then10 μl of thrombin dissolved in the starvation medium (finalconcentration: 0.1 unit/ml) was added prior to further incubation for 2days.

Upon adding 20 μl of MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) dissolvedin DPBS to 7.5 mg/ml, incubation was continued for 4 hours. The mediumwas removed by suction, 50 μl of a 10% SDS/0.029% ammonia solution wasadded, and the mixture was allowed to stand for 2 hours in a CO₂incubator for complete lysis of the cells. As an index of cellproliferation, the OD 590 nm was measured using a plate reader (EL340,BIO-TEK Instruments Inc.), and the control OD value (OD value in theabsence of the test compound) minus the OD value in the presence of thetest compound was divided by the control OD value minus the blank ODvalue (OD value without thrombin stimulation) to determine theinhibition ratio, from which the IC₅₀ value was calculated. The resultsare shown in Table 1.

TABLE 1 Ex- Rat SMC ample RBA IC₅₀ Thr IC₅₀ IC₅₀ No. Compound Compoundname (μM) (μM) (μM) Ex-ample 1

1-(3,5-di-tert-butyl-4-hy-droxy-phenyl)-2-[3-(3-eth-yl-pentyl-2-imino-2,3-di-hydro-imidazol-1-yl]-ethanonehydrobromide 0.074 0.54 0.3 Ex-ample 2

2-[3-benzyl-2-imino-2,3-di-hydro-imidazol-1-yl]-1-(3,5-di-tert-butyl-4-hydroxy-phenyl)-ethanonehydrobromide 0.25 2.4 0.96

The compounds of the present invention and salts thereof exhibitedexcellent thrombin receptor binding capacity in Test Example 1, andespecially selective binding capacity with PAR1 thrombin receptor. Inaddition, the compounds of the invention and salts thereof exhibitedexcellent platelet aggregation inhibitory action in Test Example 2. Thecompounds of the invention and salts thereof also exhibited excellentsmooth muscle cell proliferation inhibitory action in Test Example 3.

INDUSTRIAL APPLICABILITY

The present invention provides novel 2-iminoimidazole derivativesrepresented by the formula (I) and salts thereof. The compounds of theinvention represented by the formula (I) and salts thereof exhibitexcellent thrombin receptor antagonism and especially selectiveantagonism for PAR1 thrombin receptors. The compounds of the inventionand salts thereof can therefore inhibit cellular response to thrombinwhich includes platelet aggregation, without inhibiting the catalyticactivity of thrombin which converts fibrinogen to fibrin, and can alsoinhibit vascular smooth muscle proliferation occurring as a result ofdamage to vascular walls by coronary angioplasty and the like, based onselective inhibition of PAR1.

Thus the compounds of the invention and salts thereof are useful asthrombin receptor antagonists (especially PAR1 thrombin receptorantagonists), platelet aggregation inhibitors (antithrombotic agents)and smooth muscle cell proliferation inhibitors, while also being usefulas therapeutic or prophylactic agents for restenosis during or followingangioplasty, unstable angina, stable angina, myocardial infarction,cerebral infarction, peripheral arterial occlusion and the like, astherapeutic or prophylactic agents for venous thromboses such as deepvenous thrombosis, pulmonary embolism and cerebral embolism accompanyingatrial fibrillation, glomerulonephritis and the like, asanti-inflammatory agents or as anti-restenosis agents.

1. A compound having the structure:

or salt thereof; wherein R¹, R² and R³ may be the same or different andeach independently represents (1) hydrogen, (2) cyano, (3) halogen or(4) a group selected from Substituent Group A; and R¹ and R² may bondtogether to form a 5-membered ring; R⁶ represents (1) hydrogen, (2) C₁₋₆alkyl, (3) acyl, (4) carbamoyl, (5) hydroxyl, (6) C₁₋₆ alkoxy, (7) C₁₋₆alkyloxycarbonyloxy, (8) C₃₋₈ cycloalkyl, (9) C₁₋₆ alkyloxycarbonyloptionally substituted with acyloxy or (10) a C₆₋₁₄ aromatic hydrocarbonring group; wherein each of the foregoing groups is optionallysubstituted with at least one group selected from Substituent Group E;Y¹ represents —(CH₂)_(m)—; wherein m represents an integer of 1 to 3; Y²represents —CO— or —C(═N—OH)—; and Ar represents: (1) hydrogen, (2) agroup represented by the formula:

wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are the same or different and eachindependently represents (1) hydrogen, (2) cyano, (3) halogen, (4) nitroor (5) a group selected from Substituent Group B; wherein SubstituentGroup A is selected from the group consisting of C₁₋₆ alkyl, alkylidene,C₂₋₆ alkenyl, C₂₋₆ alkynyl, acyl, carboxyl, carbamoyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyloxy, amino, C₁₋₆ alkylamino, C₃₋₈ cycloalkylamino, acylamino,sulfonylamino, sulfonyl, sulfamoyl, C₃₋₈ cycloalkyl, a 5- or 6-memberednon-aromatic heterocyclic group, a C₆₋₁₄ aromatic hydrocarbon ring groupand a 5- or 6-membered aromatic heterocyclic group, wherein each of theforegoing groups is optionally substituted with at least one groupselected from Substituent Group A′; wherein Substituent Group A′represents moieties selected from the group consisting of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, cyano, acyl, carboxyl, carbamoyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyloxy, amino, C₁₋₆ alkylamino, C₃₋₈ cycloalkylamino, acylamino,ureido, ureylene, sulfonylamino, sulfonyl, sulfamoyl, halogen, C₃₋₈cycloalkyl, a heterocyclic alkyl group, a 5- or 6-membered non-aromaticheterocyclic group, a C₆₋₁₄ aromatic hydrocarbon ring group and a 5- or6-membered aromatic heterocyclic group, wherein the C₆₋₁₄ aromatichydrocarbon ring group and the 5- or 6-membered aromatic heterocyclicgroup may be substituted with at least one group selected from the groupconsisting of C₁₋₆ alkyl, cyano, acyl, carboxyl, carbamoyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyloxy, nitro, amino, C₁₋₆ alkylamino, C₃₋₈ cycloalkylamino,acylamino, ureido, ureylene, sulfonylamino, sulfonyl, sulfamoyl, halogenand C₃₋₈ cycloalkyl; Substituent Group B is selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, acyl, carboxyl,carbamoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl, C₁₋₆alkoxy, C₃₋₈ cycloalkyloxy, amino, C₁₋₆ aminoalkyl, C₁₋₆ alkylamino,C₃₋₈ cycloalkylamino, acylamino, ureido, sulfonylamino, sulfonyl,sulfamoyl, C₃₋₈ cycloalkyl, and a C₆₋₁₄ aromatic hydrocarbon ring group;wherein each of the foregoing groups is optionally substituted with atleast one group selected from Substituent Group B′; wherein SubstituentGroup B′ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, oxo, cyano, C₁₋₆ cyanoacyl, C₂₋₇ acyl, C₁₋₆alkanoyl, benzoyl, aralkanoyl, C₁₋₆ alkoxyalkylcarbonyl, C₁₋₆hydroxyalkylcarbonyl, carboxyl, C₁₋₆ carboxyalkyl, C₁₋₆ carboxyalkyloxy,carbamoyl, carbamoylalkyloxy, C₁₋₆ alkoxycarbonyl, C₁₋₁₀alkoxycarbonyl-C₁₋₆ alkyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₆ alkyloxy, C₁₋₆monoalkylaminocarbonyl, C₂₋₆ dialkylaminocarbonyl, hydroxyl, C₁₋₆alkoxy, C₁₋₁₀ alkoxyalkyl, C₁₋₁₀ aralkyloxyalkyl, C₁₋₆ hydroxyalkyl,C₃₋₈ cycloalkyloxy, amino, C₁₋₆ alkylamino, C₃₋₈ cycloalkylamino,acylamino, ureido, ureylene, C₁₋₆ alkylsulfonylamino,phenylsulfonylamino, C₁₋₆ alkylsulfonyl, phenylsulfonyl, C₁₋₆monoalkylaminosulfonyl, C₂₋₆ dialkylaminosulfonyl, sulfamoyl, halogeno,C₃₋₈ cycloalkyl, a C₆₋₁₄ aromatic hydrocarbon ring group, wherein theC₆₋₁₄ aromatic hydrocarbon ring group, may be substituted with at leastone group selected from the group consisting of C₁₋₆ alkyl, oxo, cyano,acyl, carboxyl, carbamoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,hydroxyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyloxy, nitro, amino, C₁₋₆aminoalkyl, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₃₋₈ cycloalkylamino,acylamino, ureido, ureylene, alkylsulfonylamino, alkylsulfonyl,sulfamoyl, halogeno and C₃₋₈ cycloalkyl; and Substituent Group Eselected from the group consisting of C₁₋₆ alkyl, cyano, acyl, carboxyl,carbamoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl, C₁₋₆alkoxy, C₃₋₈ cycloalkyloxy, amino, C₁₋₆ alkylamino, C₃₋₈cycloalkylamino, acylamino, ureido, ureylene, sulfonylamino, sulfonyl,sulfamoyl, halogen and C₃₋₈ cycloalkyl.
 2. A compound of claim 1,wherein R¹, R² and R³ may be the same or different and eachindependently represents C₁₋₆ alkyl, C₂₋₆ alkenyl or C₁₋₆ alkoxy;wherein each of the foregoing groups is optionally substituted with atleast one group selected from Substituent Group A″; wherein SubstituentGroup A″ represents moieties selected from the group consisting of C₁₋₆alkyl, acyl, carboxyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,hydroxyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, a C₆₋₁₄ aromatic hydrocarbonring group and a 5- or 6-membered aromatic heterocyclic group, whereinthe C₆₋₁₄ aromatic hydrocarbon ring group and the 5- or 6-memberedaromatic heterocyclic group may be substituted with at least one groupselected from the group consisting of C₁₋₆ alkyl, carboxyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, nitro,C₁₋₆ alkylamino, acylamino, sulfonylamino and halogen; R⁶ represents agroup selected from the group consisting of hydrogen, C₁₋₆ alkyl andC₁₋₆ alkyloxycarbonyl optionally substituted with acyloxy; Y² represents—CO—; and Ar represents hydrogen or a group represented by the formula:

wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are the same or different and eachindependently represents a group selected from the group consisting ofhydrogen, C₁₋₆ alkyl, hydroxyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₃₋₈cycloalkylamino, acylamino, and C₁₋₆ alkyloxycarbonyloxy; wherein eachof the foregoing groups ids optionally substituted with at least onegroup selected from Substituent Group F′; wherein Substituent Group F″isselected from the group consisting of C₁₋₆ alkyl, oxo, cyano, acyl,carboxyl and C₁₋₆ alkoxy.
 3. The compound according of claim 1, whereinY¹ is —CH₂—.
 4. The compound according of claim 1, wherein Y² is —CO—.5. The compound according to claim 1, wherein Y¹ is —CH₂— and Y² is—CO—.
 6. The compound according to claim 1, wherein Ar is a group havingthe structure:

wherein R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are as defined in claim
 1. 7. Thecompound according to claim 6, wherein R¹⁰ and R¹⁴ are hydrogen.
 8. Thecompound of claim 1, wherein Ar is a group having the structure:

wherein R¹¹ and R¹³ are as defined in claim 1; and R¹⁵ represents (1)hydrogen or (2) a group selected from Substituent Group H; whereinSubstituent Group H selected from the group consisting of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, acyl, C₁₋₆ alkoxycarbonyl, aminocarbonyl,C₁₋₆ alkylaminocarbonyl, C₃₋₈ cycloalkyl, C₁₋₆ aminoalkyl, sulfonyl,C₃₋₈ cycloalkylamino, a C₆₋₁₄ aromatic hydrocarbon ring group; whereineach of the foregoing groups is optionally substituted with at least onegroup selected from Substituent Group H′; wherein Substituent Group H′is selected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, oxo, cyano, C₁₋₆ cyanoalkyl, C₂₋₇ acyl, C₁₋₆ alkanoyl, benzoyl,aralkanoyl, C₁₋₆ alkoxyalkylcarbonyl, C₁₋₆ hydroxyalkylcarbonyl,carboxyl, C₁₋₆ carboxyalkyl, C₁₋₆ carboxyalkyloxy, carbamoyl,carbamoylalkyloxy, C₁₋₆ alkoxycarbonyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₆ alkyl,C₁₋₁₀ alkoxycarbonyl-C₁₋₆ alkyloxy, C₁₋₆ monoalkylaminocarbonyl, C₂₋₆dialkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, C₁₋₁₀ alkoxyalkyl, C₁₋₁₀aralkyloxyalkyl, C₁₋₆ hydroxyalkyl, C₃₋₈ cycloalkyloxy, amino, C₁₋₆alkylamino, C₃₋₈ cycloalkylamino, acylamino, ureido, ureylene, C₁₋₆alkylsulfonylamino, phenylsulfonylamino, C₁₋₆ alkylsulfonyl,phenylsulfonyl, C₁₋₆ monoalkylaminosulfonyl, C₂₋₆ dialkylaminosulfonyl,sulfamoyl, halogeno, C₃₋₈ cycloalkyl, and a C₆₋₁₄ aromatic hydrocarbonring group, wherein the C₆₋₁₄ aromatic hydrocarbon ring group may besubstituted with at least one group selected from the group consistingof C₁₋₆ alkyl, oxo, cyano, acyl, carboxyl, carbamoyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyloxy, nitro, amino, C₁₋₆ aminoalkyl, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₃₋₈ cycloalkylamino, acylamino, ureido, ureylene,alkylsulfonylamino, alkylsulfonyl, sulfamoyl, halogeno and C₃₋₈cycloalkyl.
 9. A compound of claim 1, wherein Ar is a group having thestructure:

wherein R¹¹ and R¹⁵ are as defined in claim 1; and R¹⁶ represents (1)hydrogen or (2) a group selected from Substituent Group H, whereinSubstituent Group H is as defined in claim
 1. 10. The compound accordingof claim 1, wherein Ar is a group having the structure:

wherein R¹¹ and R¹⁵ are as defined in claim 1, and R¹⁷ and R¹⁸ are thesame or different and each independently represents (1) hydrogen or (2)a group selected from Substituent Group I; wherein Substituent Group Iselected from the group consisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, acyl, carbamoyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl,C₁₋₆ aminoalkyl, sulfonyl, sulfamoyl, C₃₋₈ cycloalkyl, and a C₆₋₁₄aromatic hydrocarbon ring group wherein each of the foregoing groups isoptionally substituted with at least one group selected from SubstituentGroup I′; wherein Substituent Group I′ is selected from the groupconsisting of C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, oxo, cyano, C₁₋₆cyanoalkyl, C₂₋₇ acyl, C₁₋₆ alkanoyl, benzoyl, aralkanoyl, C₁₋₆alkoxyalkylcarbonyl, C₁₋₆ hydroxyalkylcarbonyl, carboxyl, C₁₋₆carboxyalkyl, C₁₋₆ carboxyalkyloxy, carbamoyl, carbamoylalkyloxy, C₁₋₆alkoxycarbonyl, C₁₋₁₀ alkoxycarbonyl-C₁₋₆ alkyl, C₁₋₁₀alkoxycarbonyl-C₁₋₆ alkyloxy, C₁₋₆ monoalkylaminocarbonyl, C₂₋₆dialkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, C₁₋₁₀ alkoxyalkyl, C₁₋₁₀aralkyloxyalkyl, C₁₋₆ hydroxyalkyl, C₃₋₈ cycloalkyloxy, amino, C₁₋₆alkylamino, C₃₋₈ cycloalkylamino, acylamino, ureido, ureylene, C₁₋₆alkylsulfonylamino, phenylsulfonylamino, C₁₋₆ alkylsulfonyl,phenylsulfonyl, C₁₋₆ monoalkylaminosulfonyl, C₂₋₆ dialkylaminosulfonyl,sulfamoyl, halogeno, C₃₋₈ cycloalkyl, a C₆₋₁₄ aromatic hydrocarbon ringgroup, wherein the C₆₋₁₄ aromatic hydrcarbon ring group, may besubstituted with at least one group selected from the group consistingof C₁₋₆ alkyl, oxo, cyano, acyl, carboxyl, carbamoyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylaminocarbonyl, hydroxyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyloxy, nitro, amino, C₁₋₆ aminoalkyl, C₁₋₆ alkylamino, C₁₋₆dialkylamino, C₃₋₈ cycloalkylamino, acylamino, ureido, ureylene,alkylsulfonylamino, alkylsulfonyl, sulfamoyl, halogeno and C₃₋₈cycloalkyl.
 11. The compound of claim 1, having the structure:


12. The compound of claim 1, having the structure:


13. The compound of claim 1, having the structure:


14. The compound of claim 1, having the structure:


15. The compound of claim 1, having the structure:


16. The compound of claim 1, having the structure:


17. The compound of claim 1, having the structure:


18. The compound of claim 1, having the structure:


19. The compound of claim 1, having the structure:


20. The compound of claim 1, having the structure:


21. A composition comprising a compound according to claim 1 and apharmaceutically acceptable carrier or diluent.
 22. A method fortreating thrombosis, vascular restenosis and/or, deep venous thrombosis,in a patient compromising administering to the patient in need thereofan amount of a compound of claim 1 or a composition of claim 21effective to antagonize a thrombin receptor.
 23. The method of claim 22wherein the thrombin receptor is a PAR1 thrombin receptor.